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Published in final edited form as: Clin Perinatol. 2020 Feb 20;47(2):399–412. doi: 10.1016/j.clp.2020.02.002

Transfusion related gut injury and NEC

Allison Thomas Rose 1, Vivek Saroha 2, Ravi Mangal Patel 3
PMCID: PMC7245583  NIHMSID: NIHMS1580690  PMID: 32439119

SYNOPSIS

Necrotizing enterocolitis (NEC) accounts for 10% of deaths in neonatal intensive care units. With the pathogenesis of NEC being multifactorial, several distinct etiologic mechanisms are likely to lead to a final common disease phenotype. The association between NEC, red blood cell (RBC) transfusion and anemia has been investigated in multiple observational studies. Although up to one-third of NEC cases occur with temporally antecedent RBC transfusion exposure, relatively few cases of NEC occur within 48 hours following RBC transfusion. This review aims to summarize recent data on NEC following RBC transfusion, with a focus on the most recent literature and ongoing trials. We highlight potential mechanisms from pre-clinical and human physiologic studies. We also discuss what is known about the role of feeding during RBC transfusion and the risk of NEC. Ongoing randomized trials will provide important data on how liberal or conservative approaches to RBC transfusion influence the risk of NEC.

Keywords: Preterm, Transfusion, Anemia, Feeding, Morbidity

Introduction

Necrotizing enterocolitis (NEC) causes significant morbidity and mortality in infants, accounting for 10% of deaths in neonatal intensive care units.1 Multiple randomized trials and observational studies have identified a variety of factors associated with NEC, although the causal effects of many of these factors is unclear.2 As NEC is a multifactorial disease, there are likely several distinct etiologic mechanisms leading to a final common disease phenotype, with intestinal inflammation a common central theme in the pathogenesis of NEC. The association between NEC, red blood cell (RBC) transfusion and anemia has been investigated in multiple observational studies.

Meta-analysis of these studies have found conflicting results with a 2012 analysis suggesting an increased odds of NEC after RBC transfusion [odds ratio (OR) 2.01, 95% confidence interval (CI) 1.61–2.5]3 and a more recent analysis suggesting no association [OR 0.96, 95% CI 0.53–1.71].4 While up to one-third of NEC cases occur in the setting of antecedent RBC transfusion exposure,5 very few cases of NEC occur within 48 hours of RBC transfusion (0.5–1.4%).6,7 Two recent animal studies may help illuminate the biological mechanisms underlying the associations between anemia, RBC transfusion and gut injury.8,9 This review aims to summarize the most recent data on NEC following RBC transfusion, which some groups have termed transfusion-related acute gut injury (TRAGI) or transfusion-associated NEC (TANEC). We also highlight the potential mechanisms in pre-clinical and human physiologic studies. As enteral feeding, including the type of feeding, may influence the risk of NEC, we review what is known about the role of feeding during RBC transfusion and the risk of NEC. While publications on TRAGI extend back to its first description in 1987 by McGrady et al,10 this review is limited to the most recent publications as well as discussions of ongoing trials. Although studies in the review use different terminology to define NEC in relation to an antecedent RBC transfusion, we will consistently use TRAGI to refer to NEC that occurs within 48 hours of RBC transfusion, and note when studies look at NEC occurring at different time-points following RBC transfusion. This is partially given the 48 hour cut-off of NEC occurring following RBC transfusion is arbitrary.

Meta-analysis of observational studies of RBC transfusion and NEC

Five meta-analysis over the past 7 years have collected data from 28 unique observational studies to try to determine the association between RBC transfusion and NEC. A systematic review and meta-analysis from 2012 reported on 12 trials (publication years 2006–2011) assessing the association of transfusion and NEC. In 5 of 12 studies reporting unadjusted outcomes, the analysis found an association between RBC transfusion and NEC with OR 3.91, 95% CI 2.97–5.14. This point estimate was attenuated when examining 4 of the 12 studies that reported adjusted outcomes: OR 2.01, 95% CI 1.61–2.50.3 Also published in 2012, a second review examined data from randomized controlled trials (RCTs) of transfusion thresholds (see discussion below) as well as observational data from 6 cohort studies and 4 case-control studies. While the pooled OR and confidence interval for RCT data remained non-significant (OR 1.67, 95% 0.82–3.38), the study noted the pooled point-estimate was in the direction toward more NEC in the restrictive transfusion group, suggesting the opposite of what would be expected if RBC transfusions alone were causative for NEC.11 The pooled estimate from randomized trials in this review were in the opposite direction of the pooled estimates from observational cohort studies (OR 7.48, 95% CI 5.87, 9.53) and case-control studies (OR 2.19, 95% CI 1.52, 3.17).11 Thus, the authors concluded that the observational data is hypothesis-generating in that it identifies a potential etiology of NEC that deserves further study, but it is not conclusive of a causal relationship between RBC transfusion and NEC.

Three additional meta-analyses published 6 years on from these first two suggest there is continued uncertainty regarding the causal association between RBC transfusion and NEC. In 2017, a Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis of clinical data on transfusions and NEC suggested that the overall quality of evidence was “low” to “very low” in the association between RBC transfusion and NEC.12 This study found no increased odds of TRAGI based on 13 observational studies (OR 1.13, 95% CI 0.99, 1.29), but and increased odds for NEC any time after transfusion (OR 1.95, 95% CI 1.60, 2.38, 9 studies). Two additional meta-analyses noted two different conclusions: a meta-analysis of 17 observational studies found no association between RBC transfusion and NEC (OR 0.96, 95 CI 0.53–1.17)13 and a meta-analysis of 10 studies found RBC transfusion was associated with a lower risk of NEC (OR 0.55, 95% CI 0.31–0.98).14 While attempts to summarize the evidence through systematic-reviews and meta-analyses have led to different estimates of the association between RBC transfusion and NEC, all meta-analyses note the inherent limitations of observational data, with bias and confounding by indication that limits causal inference. As such, data from large, ongoing randomized controlled trials will provide important information, as discussed below.

Data from RBC transfusion trials

RCT data on restrictive versus liberal transfusion thresholds have not indicated that more liberal RBC transfusion approaches increase the risk of NEC. The Premature Infants in Need of Transfusion (PINT) trial15 randomized 451 infants < 1000g and < 31 weeks gestational age to either restrictive or liberal transfusion thresholds. In the PINT trial16 the mean hemoglobin difference between the two study arms was approximately 1 g/dL with a mean hemoglobin level of 10.1mg/dL in the restrictive arm at 4 weeks compared to 11.2 mg/dL in the liberal arm. The differences in transfusion thresholds resulted in a mean difference [MD] in number of transfusions of −0.83, 95% CI −1.68–0.02, p=0.07. There was no statistically significant difference in the risk of NEC between the two study arms. The Iowa trial randomized 100 infants to restrictive or liberal transfusions and achieved a mean difference in hemoglobin of 2.7 g/dL between study arms.17 A single episode of NEC occurred in each study arm.18 A 2011 Cochrane Review pooled analysis from three RCTs of restrictive versus liberal transfusion practices, including the PINT and Iowa trials, and found no difference in the risk of NEC (RR 1.62, 95% CI 0.82–3.13); the PINT trial accounted for 90% of the weighted result.18 NEC was not the primary outcome in any of the randomized trials, and none reported on a temporal relationship between RBC transfusion and NEC. Two future RCTs comparing restrictive versus liberal transfusion thresholds will report on survival and ~2-year neurodevelopmental outcomes with NEC as a secondary outcome. In the United States, the Transfusion of Prematures (TOP) trial from the NICHD Neonatal Research Network has completed enrollment of 1824 infants randomized to restrictive versus liberal transfusion thresholds based on postnatal age and respiratory support.19 In Germany, The Effects of Transfusion thresholds on Neurocognitive Outcome of Extremely Low Birth-Weight Infants (ETTNO) trial has enrolled 920 infants with similar design to TOP.20 Together these studies may contribute information from approximately 2,700 infants to update current evidence from past-trials that will be important in guiding transfusion decisions and how such decisions may influence the risk of NEC as well as other important outcomes such as death or long-term neurodevelopmental impairment.

Role of underlying severity of anemia

Premature infants are at risk for severe anemia due to several endogenous (i.e. decreased erythropoietin production and increased EPO catabolism)21 as well as exogenous factors (i.e. iatrogenic blood loss, nutritional deficiencies, infection, chronic illness). Recent trends in clinical practice have moved away from frequent RBC transfusions to treat anemia of prematurity;22 however, it has been proposed that anemia leading to decreased oxygen delivery and tissue hypoxia may cause intestinal injury in the premature infant; thus, setting up the potential for the development of NEC. A 2011 case-control study of 333 premature infants (111 with NEC and 222 matched controls without) found a 10% increase risk of NEC for every 1 g/dL decrease in hemoglobin nadir in multivariate modeling, (OR 1.10, 95% CI 1.02–1.18).23 In a prospective study of 598 very low birth weight infants, infants with severe anemia (≤ 8g/dL) had a significantly increased rate of NEC compared to those without severe anemia (adjusted cause-specific hazard ratio (CSHR) 6.0 ,95% CI, 2.00–18.0).7 In the same study, an analysis of 319 VLBW infants who received at least 1 RBC transfusion found no association between RBC transfusion and NEC; however, severe anemia continued to be a risk factor after adjustment for other confounding variables (CSHR 6.32, 95% CI 1.94, 20.06).

Untangling the relationship between RBC transfusion, anemia and NEC is challenging as RBC transfusion is often a treatment for anemia. In observational studies, it may be difficult to distinguish whether anemia and the resulting RBC transfusion preceded the onset of NEC or was in response to the development of symptoms associated with NEC. In addition, assessing the statistical interaction between RBC transfusion and anemia on the risk of NEC requires a much larger sample size than examining each exposure alone.24 While larger RCTs are ongoing (see prior discussion of TOP, ETTNO and below for WHEAT), pre-clinical animal studies may give insight into the interaction of RBC transfusion and anemia, and the mechanisms by which such exposures might result in intestinal injury. Although animal studies may not perfectly model the human preterm gut or the development of NEC, they offer information on plausible biologic mechanisms through which anemia or RBC transfusion may influence intestinal injury that could predispose to NEC. Two recent studies focus specifically on anemia and the combination of anemia and RBC transfusion, as discussed below.8,9

Pre-clinical studies of anemia and RBC transfusion

Development of NEC is the final outcome of multiple etiologic factors, the combination of which leads to the development of signs, symptoms, and intestinal pathology consistent with the diagnosis. Progressive tissue inflammation and disruption of intestinal mucosal integrity are considered important mechanisms for the development of intestinal injury that may predispose an infant to NEC. Changes to intestinal circulation in response to anemia and blood transfusion have the potential to cause tissue hypoxia and re-oxygenation which are possible stimulants for gut inflammation and mucosal barrier damage.25,26 (Figure 1)

Figure 1. Potential mechanisms that may explain the intestinal inflammation or injury resulting from anemia and RBC transfusion.

Figure 1.

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Abbreviations: ET1, endothelin 1; NO, nitric oxide; Th, T helper cell; TLR-4, toll-like receptor 4. Adapted from Saroha V, Josephson CD, Patel RM. Epidemiology of Necrotizing Enterocolitis: New Considerations Regarding the Influence of Red Cell Transfusions and Anemia. Clin Perinatol. 2019 Mar;46(1):101–117; with permission.

Effect of anemia and transfusion on gut vasculature

Following birth, the intestines increase metabolic activity from feeding that may influence susceptibility to perturbations in oxygen delivery.27 Oxygen delivery to tissues is dependent on hemoglobin, cardiac output, vascular tone and tissue demand. Decreasing blood hemoglobin concentrations lead to circulatory adjustments, such as increases in cardiac output, capillary perfusion and increased oxygen extraction by tissues.28 Progressive anemia in newborn lambs has been shown to be associated with compensatory mechanisms including increase in oxygen extraction to maintain tissue oxygen consumption.29,30 However, profound anemia may overwhelm the body’s compensatory mechanisms, and resulting decreases in oxygen delivery may induce direct tissue hypoxia and ischemia when oxygen supply does not meet demand.31,32 Histologically, such hypoxic changes have been demonstrated in the intestinal lamina propria of anemic murine pups.8 The presence of systemic changes such as hypotension, hypoxemia, and lower oxygen saturation targeting may further compound the effect of anemia on tissue oxygen delivery.31,33,34

Intestinal circulation is governed by a dynamic balance between vasoconstrictive (catecholamine and endothelin) and vasodilatory mediators (nitric oxide, NO).35 Neonatal intestinal circulation is predominantly regulated by endothelium-derived NO (eNO)36 which is present in increased concentration as compared to mature infants. Furthermore, NO inhibition in neonates is associated with a greater increase in vascular resistance as compared to mature infants. RBC transfusion has the potential to disrupt the balance of vascular tone as demonstrated in a model of preterm lambs where, in comparison to controls, mesenteric arterial rings isolated from lambs following transfusion with RBCs demonstrated increased vasoreactivity associated with decreased expression of mesenteric arterial eNOS protein.37 Stored RBCs are known to have declining amounts of constitutive vasodilator components such as S-nitrosothiol,38 release of intracellular arginase which deplete the NO precursor arginine39 and increased free hemoglobin which binds to free NO,40 all potentially contributing to increased vasoreactivity following blood transfusion. Studies using near-infrared spectroscopy (NIRS) to measure regional tissue oxygen saturation (rSO2) have shown greater fluctuation and decreases in mesenteric oxygen patterns in infants who developed NEC post-transfusion compared to infants who were transfused and did not develop NEC.41

Effect of anemia on gut inflammation and barrier function

In a murine model examining the effects of anemia on the neonatal gut, phlebotomy induced anemia (PIA) in P8 murine pups (term-equivalent structural and functional gut maturity by P18–2142) to a mean hematocrit of <25% as compared to mean hematocrit of 45% in controls did not lead to increased hypoxia at the villous level (measured by hydroxyprobe, a marker of tissue hypoxia) and increased expression of multiple pro-inflammatory cytokines in the macrophages isolated from intestinal lamina propria, including TNF-alpha and IF-gamma.8 This was associated with increased intestinal barrier permeability and decreased tight junction protein expression, with reduction in abnormalities following macrophage depletion. This study suggests intestinal macrophages play an important role in anemia-induced inflammation, with findings confirmed by another recent study as described below9.

Interaction between RBC transfusion and anemia on gut inflammation and injury

A recent murine study examined the interaction between anemia and RBC transfusions and the underlying mechanisms that could explain the potential influences on intestinal injury.9 In this study, PIA in P13 mice pups (mean hematocrit 22.5 versus native controls hematocrit of 45%) resulted in increased intestinal permeability in anemic mice and anemic mice who received RBC transfusion compared to non-anemic controls and non-anemic transfused mice. Both anemic and anemic-transfused mice expressed additional pro-inflammatory macrophage populations but only those with exposure to both anemia and RBC transfusion displayed increased activation of macrophages and manifested biomarker and histologic evidence of gut-injury. Native controls and non-anemic RBC transfused mice did not demonstrate such macrophage infiltration, activation or associated gut injury. In addition, protection against the development of gut injury in this model was demonstrated following chelation of RBC degradation products with haptoglobin, absence of Toll-like receptor-4 (TLR4) and macrophage depletion suggesting these may be obligatory in the pathway of gut-injury in this model. A dose-response to the severity and duration of anemia was noted with increasing severity of bowel injury in the setting of more severe and prolonged anemia.

Worsening gut injury following RBC transfusion in the presence of severe anemia or prolonged anemia in the above model indicates progressive susceptibility caused by a priming step (anemia) and activation step (RBC transfusion) to induce bowel injury9. It is plausible that other factors such as an altered microbiome43 secondary to antibiotics use, formula feeds, or mucosal exposure to substrates and hypoxia26 may in combination, or independently, provoke immunological shifts44 and increase the susceptibility of the gut to injury and, potentially NEC, that is similar to the effects of anemia. Additional preclinical models that investigate combination of such factors, in addition to varying levels of oxygenation, may help better understand how anemia and/or RBC transfusion interact with other mediators to influence gut injury in the preterm infant.

Influence of feeding during RBC transfusion

Given the potential increased risk of NEC following RBC transfusion, several observational studies and a small RCT have investigated the effect of feeding during RBC transfusion on the risk of NEC. In a retrospective case-control study of 100 infants ≤ 34 weeks gestational age with NEC (Bell Stage 2A or greater), infants who developed TRAGI were more likely to be NPO compared to infants that developed NEC remote from transfusions (84.6% vs 36.8%, p < 0.001); however, there was no standard feeding protocol or approach to feeding during transfusions during the 9 year study period.45 Another study evaluated the impact of a peri-transfusion feeding protocol, comparing infants ≤ 1500 g who were NPO during all RBC transfusions to those who were fed at least once during any transfusion46. They found no difference in the risk of NEC between the two groups (5/64 vs 16/116, adjusted OR (aOR) 0.54, 95% CI 0.16–1.51). Of the 21 infants in the study who developed NEC, 11 did so within 48 hours of a transfusion; 6 infants were fed during the pre-diagnosis transfusion and 5 were NPO for a prolonged period. When infants with TRAGI were compared to a control group of transfused infants who did not develop NEC, there was no difference in the rate of NPO during transfusions or in the feeding rate (ml/kg/day) just prior to diagnosis.47

The implementation of standardized feeding protocols has been associated with a decrease in the risk of NEC.48 Several studies have reported NEC outcomes after standardization of feedings around RBC transfusions. The results, primarily from single-centers, report some conflicting data. An early 2011 study from a single institution reported a decrease in overall NEC incidence from 18 months prior to 18 months after implementation of a feeding protocol holding feeds before and during RBC transfusions (NEC incidence 5.3% [before] vs 1.3% [after], p=0.047).49 The authors recognize that their observation period may not have been long enough to identify a true trend. A quality improvement (QI) initiative that involved conservative feeding during RBC transfusion and indomethacin administration reported an overall decrease in NEC from 8.0% to <4.0%.50 However, transfusion feeding guidelines were only a portion of the QI interventions, and they were implemented at the same time as an initiative to feed mother’s own milk or donor milk early in a standardized fashion. The investigators succeeded in increasing the percentage of discharged infants fed mother’s milk prior to day of life 3 from 0% to 50% over the course of the project. This improvement alone could have a major effect on declines in NEC incidence, and, thus, it is not possible from the data presented to determine the independent effect of the peri-transfusion feeding guideline on overall reductions in NEC incidence. In another study of pre/post feeding protocol implementation, breast milk feedings increased but there was no change in rates of NEC or TRAGI despite the emphasis on early breast milk feeds and holding feeds for 12–24 hours during RBC transfusion;51 the study did find a trend towards more bloodstream infection during the epoch in which feeds were held for transfusion (3/189 pre-feeding protocol vs 11/192 post-feeding protocol with feeds held, p=0.053). Another single institution pre/post feeding protocol study demonstrated a decrease in the rate of TRAGI although the protocol itself did not address feeding practices during transfusions, but emphasized prolonged NPO times up to 14 days of life, trophic feeds for up to 7 days of life and slow advancement of enteral feeds with full feeds (150ml/kg/day) not established until 44–52 days of life.52 A regional case-crossover trial found no association between feed fortification (OR 1.67, 95% CI 0.61, 4.59), feed volume increase (OR 0.63, 95% CI 0.28, 1.38) or RBC transfusion (OR 1.8, 95% CI 0.60, 5.37) on the odds of developing NEC.53 In this study, infants served as their own control with the 48 hours before NEC onset defined as the hazard period and the 48 hours prior to the hazard period defined as the control period. Institutional practice was to hold feeds during transfusions and not to advance volume or calories on the day of transfusion. Thus, conservative feeding practices were already adopted as standard practice. A 2017 systematic review and meta-analysis examined a combination of abstracts and published articles reporting the effects of before and after results of peri-transfusion feeding policies.54 While the review concludes that withholding feeds around the time of transfusion reduced the incidence of TRAGI (RR 0.47, 95% CI 0.28, 0.80), the study’s dependence on unadjusted, observational data limits the certainty with which its conclusion can be accepted due to the possibility of residual confounding by other changes over the study periods.

The above studies, with their wide variation in protocols as well as differing outcomes on overall NEC and TRAGI rates, make it difficult to determine the best feeding practice around RBC transfusions. This is particularly relevant as relatively few cases of NEC occur within 48 hours of RBC transfusion (0.5–1.4%).6,7 At this time, there is one small RCT that examined whether withholding feeding during RBC transfusion decreases the risk of TRAGI.55 The study population constituted hemodynamically stable preterm infants ≤32 weeks gestation and ≤1500g at birth who were tolerating 130–180 ml/kg/day of enteral feeds. In addition, infants with anomalies, severe hypoxia, asphyxia, and those who received RBC transfusion in the first 7 days of life were excluded. RBC transfusions were given per an established unit protocol. Infants were randomized to an NPO group (1–2 feeds held before, during, and after transfusion resulting in 8–12 hours of NPO time) or a FED group (feeds continued as per established unit feeding protocol). The study’s primary outcomes were an increase in abdominal circumference and NEC development in the first 72 hours after transfusion. 112 infants were randomized, 52 in the NPO group and 58 in the FED group at which point no further randomization occurred due to low NEC rates and futility. There was no difference between the two groups in abdominal circumference, feeding intolerance, or NEC. The combined outcome of feeding intolerance and/or NEC and mortality was significantly higher in the FED group (17.2% vs 1.9%, p=0.009) with a trend to increase mortality in the FED group (0 vs 6.8%, p=0.06). However, these results should be interpreted with caution because the study was stopped early and underpowered to detect such differences in mortality. A pilot point-of-care RCT, Withholding Enteral feeds Around packed RBC Transfusion (WHEAT) has finished initial enrollment in the United Kingdom (https://www.npeu.ox.ac.uk/wheat) and may expand to a larger, multicenter trial in the United Kingdom or elsewhere. This trial randomizes infants born at < 30 weeks gestation to either continue enteral feedings during RBC transfusion or to withhold feeds for 4 hours prior to, during, and 4 hours after the transfusion. This trial should provide further information to guide feeding practices during RBC transfusions, including effects on NEC as well as other important outcomes such as late-onset infection.

Use of Near-Infrared Spectroscopy Monitoring

As approaches to RBC transfusion and feeding during RBC transfusion in the aforementioned studies are applied broadly to preterm infants, tools such as NIRS may provide some insight into the effect of anemia, RBC transfusion and feeding on intestinal oxygenation for an individual infant. The use of NIRS monitoring of splanchnic rSO2 during feeding has been reported in several studies. Infants with feeding intolerance were noted to have lower splanchnic rSO2 or splanchnic to cerebral oxygenation ratio (SCOR), a measure of relative intestinal oxygenation.27,56 In addition, bolus feeds seem to result in increased superior mesenteric artery velocity as measured by Doppler and rSO2 as measured by NIRS that is not seen in the setting of continuous feeds.57–59 In a study of 50 anemic preterm infants (Hct ≤ 28%), the SCOR decreased from baseline during feedings and splanchnic rSO2 trended toward decreased levels during feedings. In addition, after feeding there was not an increase in splanchnic rSO2 as demonstrated in other feeding studies.32 These findings suggest that anemic infants may have less ability to meet the metabolic demand of feeding and digestion, potential making them more vulnerable to the consequences of imbalanced oxygen demand and supply. However, there is currently insufficient evidence to support the use of NIRS to guide RBC transfusion or approaches to feeding during RBC transfusion.

Characteristics of transfused RBC products

If the transfusion of blood products has the ability to alter intestinal circulation and incite inflammatory responses based on data from pre-clinical studies, then blood banking practices, donor characteristics and RBC characteristics may influence recipient responses to transfusion. Transfusion practices for neonates vary between blood banks in terms of preservation solution used, timing of irradiating of RBCs and age of RBCs transfused.60 Little is known about whether these practices influence neonatal outcomes, including NEC. Pre-clinical data suggests transfused RBCs can introduce exogenous biological response modifiers that may play a role in gut inflammation and intestinal injury.24 In the anemic-transfused mice model developed by MohanKumar et al.,9 the inflammatory effects of RBC transfusion were isolated to factors released by stored RBCs. Increased inflammatory signaling was seen only in the setting of exposure to stored RBC product (7 day RBC or 7 day plasma with fresh RBCs),and minimal inflammation was seen with fresh RBC transfusion, fresh plasma transfusion or 7 day plasma supernatant without exposure to RBCs.9 However, 7 day old stored murine RBCs may not reflect what is transfused to human neonates. In the multicenter Age of Red Blood Cells in Premature Infants (ARIPI) trial, low birth weight infants were randomized at Canadian centers to receive transfusion of RBCs stored 7 days or less (188 infants) versus standard blood banking practice (189 infants). The study’s primary outcome was a composite of major neonatal morbidities including NEC. The mean age of transfused blood in the intervention group was 5.1 (standard deviation [SD] 2.0) days and 14.6 (SD 8.3) in the standard practice group. There was no difference in the primary outcome between the two groups (RR 1.00, 95% CI 0.82, 1.2) or in NEC alone (RR 1.00, 95% CI 0.48, 2.12).61 Therefore, there is currently no data from clinical trials that would support transfusion of only fresh RBCs into neonates. Beyond chronological storage age, the storage duration after RBC product irradiation has been shown to be negatively correlated with the magnitude of regional cerebral oxygen saturation response to RBC transfusion, suggesting the time from irradiation to RBC transfusion may influence the effect of transfused RBCs on changes in oxygen delivery.62 The impact of irradiation is currently being studied in a prospective cohort study that will examine the relationship between prolonged irradiation storage time, RBC metabolomics profiles, and anemia on intestinal oxygenation and the development of NEC in premature infants.63

Outside of RBC product transfusion, the role of platelet transfusions in the pathogenesis or propagation of NEC is unclear.64,65 Neuropeptide Y, a molecule that can play a role in splanchnic vasoconstriction as well as macrophage adhesion, was found in increasing levels in stored platelets suggesting platelet-derived active substances present in stored platelets may contribute to NEC injury65. One retrospective study found increased morbidity in preterm neonates with NEC who received greater number and volume of platelet transfusion;64 although another found no difference in platelet transfusion rate and death from NEC.65 In the Platelets for Neonatal Transfusion-Study 2 (PlaNeT-2) where infants were randomized to high (50,000/mm3) versus low (25,000/mm3) platelets transfusion threshold, 16% of infants randomized had NEC at the time of randomization, and there was no difference in additional NEC cases between the two groups.66

Summary

The impact of NEC on neonatal morbidity and mortality, as well as the concern that a common neonatal physiologic state (anemia) and intervention (RBC transfusion) may predispose premature infants to NEC, make understanding the causal effects of anemia and RBC transfusion and underlying mechanisms important to researchers and clinicians. Recently developed pre-clinical murine models that investigate the impact of anemia and RBC transfusion on gut injury are providing some insight into the observed clinical phenomenon of TRAGI. The effect of anemia and transfusion on gut barrier integrity, inflammation and tissue hypoxia may be related to alterations in endogenous vasoactive mediators, upregulation of TLR-4, and activation of pro-inflammatory macrophages. Other factors, such as transfusion product and donor characteristics, need additional studies to determine if they influence outcomes such as NEC. Additionally, ongoing trials comparing RBC transfusion thresholds and the effect of withholding of feeding during RBC transfusion will provide important information regarding how these common interventions may influence the risk of NEC and other important outcomes in preterm infants.

Best Practices

What is the current practice?

Currently, there is uncertainty about the optimal hemoglobin thresholds for RBC transfusion, the safest RBC product characteristics for preterm infants, and the best approach to enteral feeding during RBC transfusions. What changes in current practice are likely to improve outcomes?

  1. The implementation of standardized feeding protocols that including the use of human milk feedings have been associated with a reduction in the risk of NEC. Implementation of such protocols may be helpful to reduce the risk of NEC until further data from RCTs about feeding practices during RBC transfusions are available.

  2. Pre-clinical and clinical data suggest severe anemia may influence the risk of gut injury. Strategies to reduce severe anemia, such as minimizing unnecessary phlebotomy-related blood loss, provision of delayed cord clamping and avoidance of transfusion thresholds lower than those studied in trials to date are suggested care approaches, although additional studies will provide better data on the safety of tolerance of neonatal anemia.

Summary Statement

Anemia (priming step) and RBC transfusion (activating step) may play a role in gut injury. Results from ongoing RCTs of transfusion thresholds as well as feeding practices during RBC transfusion should inform important clinical decisions surrounding approaches to RBC transfusions and enteral feedings during transfusion.

KEY POINTS.

  • Pre-clinical studies have identified plausible biologic mechanisms of gut injury from RBC transfusion in the setting of anemia. These studies may explain the epidemiologic associations observed in studies of preterm infants between severe anemia, RBC transfusion, and NEC.

  • The optimal hemoglobin transfusion thresholds to reduce the risk of NEC and other important adverse outcomes in preterm infants is uncertain. Ongoing randomized trials, coupled with advanced monitoring techniques such as near-infrared spectroscopy, may provide new information to guide approaches to red cell transfusion in preterm infants.

  • The implementation of standardized feeding protocols is associated with a reduction in the risk of NEC; however, the effects of withholding feeding during RBC transfusion on NEC and other important outcomes is uncertain.

  • Additional studies are needed to further understand the effects of RBC product characteristics on transfusion-related outcomes in preterm infants.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

DISCLOSURE STATEMENT

Dr. Patel reports receiving grant support from the National Institutes of Health (K23 HL128942). The authors have no other relevant conflicts of interest to disclose.

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