Abstract
OBJECTIVE:
The study objective was to explore the relationship between necrotizing enterocolitis (NEC) and packed red blood cell (pRBC) transfusion in very low birth weight (VLBW) neonates (<1500 g).
STUDY DESIGN:
A six-year retrospective chart review of VLBW infants with NEC (Bell’s Stage > II) and a pRBC transfusion within 48 hours of diagnosis. Prenatal data, postnatal course, transfusion history, and NEC outcomes were reviewed. The transfusion associated necrotizing enterocolitis (TANEC) cases were matched with controls (1:2) who were transfused but did not develop NEC as to proximity of birth date, gestational age, and receipt of transfusion.
RESULTS:
Of 1139 VLBW admissions, there were 73 cases of NEC and 30 cases of TANEC (annual NEC rate 6.4%). TANEC cases were matched with 60 controls who were transfused but never developed NEC. Neonatal profiles were similar between all 3 groups, except for a higher proportion of infants <10th percentile in the non-TANEC group. Days of antibiotics and frequency of patient ductus arteriosus (PDA) ligation were lower in controls compared to NEC cases. Lower feeding rate at diagnosis of NEC/match were more common in control infants compared to TANEC infants. However, feeding abstinence rates were similar between the two groups. The number of transfusions prior to diagnosis/match was similar in all groups. There was no significant difference in pre-transfusion hematocrit values between the groups.
CONCLUSION:
TANEC was common among NEC cases. PDA ligation was similar among TANEC and non-TANEC but lower in controls. Similar pre-transfusion hematocrits were found among TANEC and controls. Feeding abstinence rates were also similar between TANEC and controls.
Introduction
Necrotizing enterocolitis (NEC) is a cause of profound morbidity and mortality primarily among VLBW neonates and is associated with neurodevelopmental delay [1, 2]. The financial burden is significant. Medical NEC on average adds as much as $60,000 and surgical disease up to $200,000 per patient [3]. The annual impact on the US healthcare industry has been estimated up to $1 billion dollars [3]. This however does not take into account the impact of the associated lifelong co-morbidities associated with the disease. The incidence of NEC for infants born less than 28 weeks is 10 to 12% [4]. Despite advances in the care of premature newborns and significant amounts of research dedicated to NEC, the exact pathogenesis remains unknown [5]. However, it appears to be a multifactorial disease process, which includes alteration of GI tract bacterial colonization, formula feeding and activation of inflammatory mediators [6, 7]. Over the years, there has been a concern for a temporal association between NEC and the administration of packed cell blood cells in very low birth weight (VLBW, <1500 g) infants [8–13].
The exact mechanism between packed red blood cell transfusion and subsequent gut injury and development of NEC remains highly controversial. Transfusion associated necrotizing enterocolitis (TANEC) has been defined as an association between packed red blood cell (pRBC) transfusions within a forty-eight-hour period prior to the diagnosis of NEC [9, 11]. It has been hypothesized that pRBC transfusion in VLBW infants plus simultaneous feeding increases gut metabolic demand resulting in significant gut hypoperfusion [14]. These observations have led many institutions to implement policies regarding feeding status during transfusions [8].
The purpose of this study was to further determine if transfusions were associated with cases of NEC and any factors that placed neonates at an increased risk to develop TANEC. The study included matched controls with similarly timed transfusions as TANEC patients but who never developed NEC.
Methods
Internal review board (IRB) approval was obtained prior to any data collection. Medical records were reviewed for confirmed NEC cases with pRBC transfusion within forty-eight-hours of diagnosis at Kosair Children’s Hospital (now Norton Children’s Hospital) between 2007–2012. TANEC cases (infants transfused within forty-eight-hours of NEC diagnosis; T), non-TANEC infants (NEC occurring without a history of transfusion in the previous 48 hours; non-T) and controls (infants transfused but without a diagnosis of NEC) were identified via NICU database query. Cases included all VLBW (BW <1,500 grams) infants with confirmed NEC diagnosis (Bell’s stage IIA or greater: gastric retention, abdominal distention, emesis, heme ± grossly bloody stool, absent bowel sounds ± abdominal tenderness, and intestinal dilation/ileus, pneumatosis intestinalis). Controls were matched 2:1 with TANEC cases based on similar birth times (month/year) during the six-year study period, gestational age at birth (±7–14 days), birth weight (±200 grams) and gestational age at matched transfusion (±7–14 days). Data included basic demographics, birth information, and general medical course. NEC diagnostic details and outcomes included the history of transfusions, focusing on blood products administered within forty-eight-hours of the diagnosis of NEC.
Continuous variables were analyzed by T-test or ANOVA. Bivariate data were analyzed by Chi Square. Statistical significance was set at p < 0.05.
Results
Perinatal profile
Perinatal profile
p = 0.003 control vs. TANEC and non-TANEC.
Neonatal profiles were similar between non-T cases, T cases, and controls as demonstrated in Table 1 except for the proportion of infants born <10th percentile for weight.
Medical course prior to NEC diagnosis
Medical course prior to NEC diagnosis
Medical course prior to TANEC matched transfusion.
TANEC vs Control.
non-TANEC vs. Control.
Transfusion and NEC profiles
*Matched to age at TANEC transfusion, controls did not have NEC diagnosis.
**non-TANEC vs. control.
non-TANEC vs TANEC.
TANEC vs control.
Control vs. both groups. NA (not applicable, did not develop NEC). NA (not applicable, did not receive transfusion within 48 hrs of NEC diagnosis).
Enteral feeding initiation was at 4-5 days of life and receipt of human milk (HM) as first feeding was similar between non-T and T infants (data not shown). The feeding rate at the diagnosis of NEC was lower in non-T infants compared to control infants that did not receive a diagnosis of NEC (Table 3). Control and T patients had similar rates of NPO prior to transfusion (48.1% vs 58.3%).
Details surrounding NEC diagnosis
Rates of medical and surgical NEC were similar between NEC-affected groups (p = 0.1). Mortality rates were similar in the non-T and T affected groups but significantly higher when compared to controls without NEC (Table 3).
Transfusion data
T infants received more transfusions prior to diagnosis than control infants (p = 0.029). There was no difference in pre-transfusion hematocrits (Table 3).
Discussion
As the question of the relationship between transfusions and NEC remains unsettled, this study adds an interesting component by providing a control group: infants that were transfused but did not go on to develop NEC. Infants in all 3 groups were similar at birth, except the non-TANEC group had a higher proportion of infants that were <10th percentile. Despite the similarities at birth, non-TANEC infants were significantly older and weighed more at the time of diagnosis compared to the controls. While the presence of a PDA was similar across groups, the proportion of infants that required PDA ligation was significantly higher in the TANEC group compared to the controls. It has been suggested that infants with significant PDAs receiving pRBCs are at higher risk for TANEC due to inconsistent gut perfusion [15]. There is a reduced mesenteric blood flow for up to 4 hours after a pRBC transfusion in these infants with significant PDAs [16].
Infants in the non-TANEC group were exposed to more days of antibiotics than the controls without NEC. There has been a correlation shown between increased duration of antibiotics and NEC, presumably associated with alterations in the gut microbiome [14].
Pre-transfusion hematocrits were similar across groups. Transfusion of packed red blood cells and the impact on the preterm gut is controversial. El-Dib et al., Blau et al., Singh et al., Mohamed et al., and Wan-Huen et al., suggest a temporal association while Sharma et al. and Wallenstein et al. found no association [8–11, 17]. Liberal transfusion practices have been shown to be protective against TANEC by way of avoiding low hematocrits that could lead to reperfusion injury upon transfusion [17].
Anemia has been suggested as potentially causative leading to changes in mesenteric blood flow ultimately poor tissue perfusion and gut injury [10, 19]. It has been suggested that low hematocrits were associated with an increased risk of developing NEC [10]. Hematocrits before a diagnosis of NEC were lower in TANEC patients than non-TANEC patients [9]. Other studies support the hypothesis that lower hematocrits are correlated with the development of NEC [13, 20]. Recently, an increased risk for NEC was demonstrated with severe anemia (hemoglobin of 8 g/dL or less) but showed no evidence of association with transfusion [21]. With mean hematocrits in the low thirty range, study infants were not considered severely anemic. Paul et al. reported findings similar to our study among infants developing NEC within forty-eight-hours of transfusion and those developing NEC > forty-eight-hours after transfusion, although without the benefit of a control group [20]. Our study results suggest that it may not be the hematocrit that matters but the transfusion exposure itself.
Donated RBCs undergo significant stress during the collection, preservation and storage processes [22]. Red blood cells undergo structural and metabolic changes that may have deleterious effects on gut oxygen delivery [14, 23]. Infusion of these products can lead to an inflammatory response due to release of cytokines and other pro-inflammatory substrates [14]. It has been suggested that pRBC transfusion may lead to a similar immune response in the gut as seen in transfusion-associated lung injury (TRALI) as described in adult patients [22]. Therefore, it may be the combination of a more stringent transfusion policy that may decrease TANEC and overall morbidity associated with pRBC exposure in this population.
Feeding abstinence at the time of transfusion was similar among control infants compared to TANEC infants. However, feeding rates among control infants were lower than the other 2 groups, especially compared to the non-TANEC infants. It has been proposed that enteral feeding serves as a key factor in the cascade of events leading to NEC due to increased oxygen consumption during digestion [14, 20]. Postprandial mesenteric oxygenation declines during red blood cell transfusion and feeding during pRBC transfusions may increase the risk for mesenteric ischemia and the subsequent development of TANEC [24, 25]. Studies have demonstrated a reduction in NEC after implementation of a peri-transfusion protocol [8, 19]. Feeding abstinence during a transfusion has shown a reduction of NEC development [8]. It is also well known that use of human milk over bovine milk products reduces the incidence of NEC [26, 27]. Our studied failed to show that abstinence leads to a reduction in TANEC. During our study period, there was no standardized feeding protocol but the initiation of enteral feeding with human milk was similar across groups. Our study failed to show that abstinence leads to a reduction in TANEC.
Conclusion
The six-year rate of NEC for our NICU was similar to nationally reported rates, while mortality in our cohort was lower than national benchmarks. TANEC occurred in 41% of NEC cases. Controls were less likely to have had a PDA ligation, were exposed to fewer transfusions and were exposed to fewer days of antibiotics than infants developing NEC. Stricter pRBC transfusion parameters may aid in the decrease of blood product administration and, based on our data, may be associated with a decrease in the incidence of NEC. Similar numbers of control infants and TANEC infants were feeding at the time of transfusion yet control patients did not go on to develop NEC. This contrasts with data in the literature that show correlation between NPO status and pRBC transfusion with the subsequent development of NEC. However, Non-T infants were receiving higher feeding rates than control infants. This does not clarify feeding status with a pRBC transfusion as Non-T infants did not receive a transfusion but it does question if more aggressive feeding rates put infants at risk for NEC.
Limitations of this study include the retrospective nature of the study and the single center design. TANEC patients weighed less at the time of NEC diagnosis compared to non-TANEC patients.
Prospective investigational studies are needed to establish evidence based feeding practices surrounding packed red blood cell administration as well as better transfusion guidelines.