All issues > Volume 56(3); 2013

Original Article

Published online: March 18, 2013

DOI: https://doi.org/10.3345/kjp.2013.56.3.112

Analysis of the association between necrotizing enterocolitis and transfusion of red blood cell in very low birth weight preterm infants

Seon-Yeong Bak, MD¹, Sihyoung Lee, MD¹, Jae-Hong Park, MD¹, Kyu-Hee Park, MD², Ji-Hyun Jeon, MD²

¹Department of Pediatrics, CHA Bundang Medical Center, CHA University, Seongnam, Korea.

²Department of Pediatrics, CHA Gangnam Medical Center, CHA University, Seoul, Korea.

Corresponding author: Ji-Hyun Jeon, MD. Department of Pediatrics, CHA Gangnam Medical Center, CHA University, 566 Nonhyeon-ro, Gangnam-gu, Seoul 135-913, Korea. Tel: +82-2-3468-3010, Fax: +82-2-3468-2616, goddaugh@chamc.co.kr

Received July 12, 2012       Revised August 24, 2012       Accepted October 25, 2012

Copyright © 2013 by The Korean Pediatric Society

(open-access, http://creativecommons.org/licenses/by-nc/3.0/):

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Purpose

Purpose

To investigate the association between necrotizing enterocolitis (NEC) and red blood cell transfusions in very low birth weight (VLBW) preterm infants.

Methods

Methods

We studied were 180 VLBW preterm infants who were admitted to the neonatal intensive care unit of CHA Gangnam Hospital from January of 2006 to December of 2009. The subjects were divided into 2 groups: an NEC group (greater than stage II on the modified Bell's criteria) and a control group (less than stage II on the modified Bell's critieria). We defined red blood cell transfusion before NEC diagnosis as the frequency of transfusion until NEC diagnosis (mean day at NEC diagnosis, day 18) in the NEC group and the frequency of transfusion until 18 days after birth in the control group.

Results

Results

Of the 180 subjects, 18 (10%) belonged to the NEC group, and 14 (78%) of these 18 patients had a history of transfusion before NEC diagnosis. The NEC group received 3.1±2.9 transfusions, and the control group received 1.0±1.1 transfusions before the NEC diagnosis (P=0.005). In a multivariate logistic regression corrected for gestational age, Apgar score at 1 minute, the presence of respiratory distress syndrome, patent ductus arteriosus, premature rupture of membrane, disseminated intravascular coagulopathy and death were confounding factors. The risk of NEC increased 1.63 times (95% confidence interval, 1.145 to 2.305; P=0.007) with transfusion before the NEC diagnosis.

Conclusion

Conclusion

The risk for NEC increased significantly with increased transfusion frequency before the NEC diagnosis.

Key words: Necrotizing enterocolitis, Very low birth weight infants, Red blood cell transfusion

Introduction

Introduction

Necrotizing enterocolitis (NEC) is an emergency gastrointestinal disease in neonates due to mucosal or transmural necrosis of the bowel. About 7% to 13% of all very low birth weight (VLBW) infants admitted to the neonatal intensive care unit (NICU) develop NEC, with a mortality range of 10% to 44%1-³⁾, and both the incidence and mortality rate increase with decreasing birth weight and gestational age (GA). Intestine immaturity, birth asphyxia, low appearance, pulse, grimace, activity, and respiration (Apgar) score, intestinal ischemic change due to umbilical artery catheterization, viruses (rotavirus, coronavirus, and enterovirus), infection from coagulase-negative Staphylococcus or Clostridium difficile, and early rapid feeding are cause of NEC4-⁶⁾. Some reports have indicated an association between red blood cell (RBC) transfusion (RBC(t)) and NEC, but this is controversial7-¹⁰⁾. In this study, we analyzed the association between NEC and RBC(t) in VLBW preterm infants.

Materials and methods

Materials and methods

We reviewed the charts of 180 VLBW preterm infant patients retrospectively who were admitted to the NICU of CHA Gangnam Hospital from January 2006 to December of 2009, excluding patients with hematologic disease, intraabdominal anomalies, and other congenital anomalies. Patients who received transfusions for causes other than NEC were also excluded.

The NEC diagnosis was made according to the modified Bell's staging criteria by a neonatologist when infants had both systemic and radiographic signs of NEC. Infants with stage II or greater were defined as the NEC group and those less than stage II and without NEC patients were defined as the control group. We defined that RBC(t) before NEC diagnosis as the frequency of transfusion until the NEC diagnosis (mean day at NEC diagnosis, day 18) in NEC group. Therefore, the frequency of transfusion was counted until 18 days after birth in control group. We evaluated patient history, including GA, birth weight (B.wt), Apgar score at 1 and 5 minutes, hemoglobin (Hgb) and hematocrit (Hct) at birth, the time from premature rupture of membrane (PROM), the use of prenatal antibiotics, intraventicular hemorrhage (IVH≥grade 2: identified and classified by sonographic features), disseminated intravascular coagulopathy (DIC), hemorrhage history at other sites (pulmonary hemorrhage, gastrointestinal hemorrhage, and petechia), the presence of respiratory distress syndrome (RDS), and the number of times surfactant was used, presence of patent ductus arteriosus (PDA), dose of indomethacin administration, time on ventilator and O₂ and the presence of bronchopulmonary dysplasia. We investigated the NEC stage and the frequency of packed RBC(t) during the hospital course and transfusions before the NEC diagnosis for the patients with a NEC diagnosis. The decision for RBC(t) was made by the neonatologist caring for the infant and transfusion guidelines¹¹⁾ were followed. All transfusions were done with packed RBCs. Packed RBCs were transfused in a volume of 10 to 20 mL/kg over 2 to 4 hours.

PDA was diagnosed based on echocardiographic findings. The number of transfused patients, the frequency of transfusions per patient, Hgb level at the time of transfusion, and cases in which the NEC diagnosis was made within 48 hours of transfusion were also analyzed. The Statistical analysis was performed with SPSS ver. 12.0 (SPSS Inc., Chicago, IL, USA) using the t-test, and logistic regression. P value under 0.05 was considered significant.

Results

Results

Among the 180 VLBW preterm infants, 18 (10%) were included in the NEC group. GA, B.wt, Hgb and Hct were not different between the two groups at birth. But, the Apgar scores at 1 and at 5 minutes were significantly lower in the NEC group, and the incidence of RDS, DIC, hemorrhage and mortality were also significantly higher than those in control group. The incidence of IVH and PDA tended to be more frequent in the NEC group than that in the control group. But there were no significant statistical difference. A total of 3.1±2.9 transfusions were administered in the NEC group before the NEC diagnosis with 6.2±5.8 transfusions administered in the NEC group during the entire hospital course. This number of transfusions before NEC diagnosis was significantly larger than that in the control group (1.0±1.1 times) (Table 1).

Table 2 shows the univariate logistic regression to verify generally known NEC risk factors, including Apgar score, PDA, RDS, DIC, and hemorrhage. PDA was not a significant factor and RDS had a nonsignificant confidence interval. The risk of NEC decreased significantly with higher 1 and 5 minutes Apgar scores (Table 2). The risk for NEC increased 1.22 times (95% confidence interval [CI], 1.081 to 1.395; P=0.002) for those with a higher frequency of RBC transfusion during hospital course. The risk for NEC increased 1.91 times (95% CI, 1.409 to 2.599, P=0.001) with higher the frequency of RBC(t) before NEC diagnosis (Table 2). We conducted a multivariate logistic regression after adjusting for GA, Apgar score, PDA, RDS, PROM, DIC and death. As a result, the risk for NEC increased 1.19 times (95% CI, 1.022 to 1.387; P=0.026) with increasing frequency of RBC(t) during the hospital course. The frequency of RBC(t) before NEC diagnosis increased the risk for NEC 1.63 times (95% CI, 1.145 to 2.305; P=0.007) (Table 3).

Discussion

Discussion

Late complications of the gastrointestinal system in preterm babies are increasing along with early pulmonary and cardiologic early complications. NEC remains a disease with high mortality even with aggressive treatment¹²⁾. Additionally, NEC requiring surgical treatment lead to growth and developmental disorders in VLBW infants13,¹⁴⁾. The incidence of NEC varies with reporters. According to Walsh and Kliegman¹⁵⁾, Gregory et al.¹⁶⁾, Egan et al.¹⁷⁾, and Polin et al.¹⁸⁾, NEC occurs in 0.83% to 7.5% of all infants, but according to Kliegman et al.¹⁹⁾ the incidence of VLBW infants admitted to the NICU is 12%. In this study, the incidence of NEC among the VLBW preterm infants was 10%, which was similar to other reports.

The etiology and pathogenesis of NEC is not clearly understood²⁰⁾, but it is known to be a complex, multifactorial disease21,²²⁾. According to a recent reports transfusion increase the risk for NEC⁷⁾, and the NEC mechanism is related to a recent exposure to transfusions. The latest hypotheses as to why packed RBC(t) increases the risk of NEC suggest that stored RBCs decrease nitric oxide²³⁾ and a packed RBC(t) increases the intestinal immune response²⁴⁾. In this study, GA and B.wt were not different between the NEC and control groups, but in the univariate logistic regression, the risk for NEC decreased significantly the higher the GA, B.wt, and Apgar scores at 1 and 5 minutes. Higher PDA incidences also tended to increase NEC risk, but the difference was not significant. The number of patients in the NEC group who were diagnosed within 48 hours of a transfusion was 14 and after 48 hours the number was two. Only two patients with NEC did not receive a transfusion their GA were 31 and 30 weeks and their Apgar scores at 1 minute were 1 point and 0 points. Cardiopulmonary resuscitation was carried out on these infants. The Apgar score at 5 minutes recovered to 5 points for both and the infants recovered with conservative therapy after the NEC diagnosis.

In the multivariate logistic regression, a higher frequency of RBC(t) before the NEC diagnosis increased the risk for NEC 1.63 times (95% CI, 1.145 to 2.305; P=0.007) after adjusted for GA, Apgar score at 1 minute, RDS, PROM, DIC, and death. The number of transfusions was significantly different between our two groups and the adjusted multivariate logistic regression revealed that the NEC risk increased 1.297 times (95% CI, 1.097 to 1.533; P=0.002) with an increase in the number of transfusions. There are several biologically plausible reasons why packed RBC(t) may lead to NEC, including a decrease in nitric oxide in stored RBCs and an exaggerated intestinal immune response to packed RBC(t)⁹⁾. In contrast to our study, Josephson et al¹⁰⁾. reported that RBC(t) had no temporal relationship to NEC and stated that is only meaningful as it indicates the infant's general condition.

Because many reports are contradictory on the relationship between transfusions and NEC, additional studies are necessary involving larger patient groups. In addition, the patient's general condition and the risk of NEC based on the transfusion must be considered when treating preterm infants <1,500 g.

In conclusion, we analyzed the risk factors for developing of NEC in VLBW preterm infants. The results showed that the risk for NEC increased with an increased frequency of transfusions before the NEC diagnosis (relative risk, 1.63; 95% CI, 1.145 to 2.305; P=0.007).

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

References

1. Stoll BJ. Epidemiology of necrotizing enterocolitis. Clin Perinatol 1994;21:205–218.
[Article] [PubMed] [PMC]

2. Luig M, Lui K. NSW & ACT NICUS Group. Epidemiology of necrotizing enterocolitis--Part II: Risks and susceptibility of premature infants during the surfactant era: a regional study. J Paediatr Child Health 2005;41:174–179.
[Article] [PubMed]

3. Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of necrotizing enterocolitis infant mortality in the United States. Am J Public Health 1997;87:2026–2031.
[Article] [PubMed] [PMC]

4. Brook I. Microbiology and management of neonatal necrotizing enterocolitis. Am J Perinatol 2008;25:111–118.
[Article] [PubMed]

5. Neu J. Neonatal necrotizing enterocolitis: an update. Acta Paediatr Suppl 2005;94:100–105.
[Article] [PubMed]

6. Kafetzis DA, Skevaki C, Costalos C. Neonatal necrotizing enterocolitis: an overview. Curr Opin Infect Dis 2003;16:349–355.
[Article] [PubMed]

7. Mohamed A, Shah PS. Transfusion associated necrotizing enterocolitis: a meta-analysis of observational data. Pediatrics 2012;129:529–540.
[Article] [PubMed]

8. Blau J, Calo JM, Dozor D, Sutton M, Alpan G, La Gamma EF. Transfusion-related acute gut injury: necrotizing enterocolitis in very low birth weight neonates after packed red blood cell transfusion. J Pediatr 2011;158:403–409.
[Article] [PubMed]

9. Paul DA, Mackley A, Novitsky A, Zhao Y, Brooks A, Locke RG. Increased odds of necrotizing enterocolitis after transfusion of red blood cells in premature infants. Pediatrics 2011;127:635–641.
[Article] [PubMed]

10. Josephson CD, Wesolowski A, Bao G, Sola-Visner MC, Dudell G, Castillejo MI, et al. Do red cell transfusions increase the risk of necrotizing enterocolitis in premature infants? J Pediatr 2010;157:972–978.e1-3.
[Article] [PubMed] [PMC]

11. Shannon KM, Keith JF 3rd, Mentzer WC, Ehrenkranz RA, Brown MS, Widness JA, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics 1995;95:1–8.
[Article] [PubMed]

12. Stichtenoth G, Demmert M, Bohnhorst B, Stein A, Ehlers S, Heitmann F, et al. Major contributors to hospital mortality in very-low-birth-weight infants: data of the birth year 2010 cohort of the German Neonatal Network. Klin Padiatr 2012;224:276–281.
[Article] [PubMed]

13. Martin CR, Dammann O, Allred EN, Patel S, O'Shea TM, Kuban KC, et al. Neurodevelopment of extremely preterm infants who had necrotizing enterocolitis with or without late bacteremia. J Pediatr 2010;157:751–756.e1.
[Article] [PubMed] [PMC]

14. Ta BD, Roze E, van Braeckel KN, Bos AF, Rassouli-Kirchmeier R, Hulscher JB. Long-term neurodevelopmental impairment in neonates surgically treated for necrotizing enterocolitis: enterostomy associated with a worse outcome. Eur J Pediatr Surg 2011;21:58–64.
[Article] [PubMed]

15. Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatr Clin North Am 1986;33:179–201.
[Article] [PubMed] [PMC]

16. Gregory JR, Campbell JR, Harrison MW, Campbell TJ. Neonatal necrotizing enterocolitis. A 10 year experience. Am J Surg 1981;141:562–567.
[Article] [PubMed]

17. Egan EA, Mantilla G, Nelson RM, Eitzman DV. A prospective controlled trial of oral kanamycin in the prevention of neonatal necrotizing enterocolitis. J Pediatr 1976;89:467–470.
[Article] [PubMed]

18. Polin RA, Pollack PF, Barlow B, Wigger HJ, Slovis TL, Santulli TV, et al. Necrotizing enterocolitis in term infants. J Pediatr 1976;89:460–462.
[Article] [PubMed]

19. Kliegman RM, Pittard WB, Fanaroff AA. Necrotizing enterocolitis in neonates fed human milk. J Pediatr 1979;95:450–453.
[Article] [PubMed]

20. Hsueh W, Caplan MS, Qu XW, Tan XD, De Plaen IG, Gonzalez-Crussi F. Neonatal necrotizing enterocolitis: clinical considerations and pathogenetic concepts. Pediatr Dev Pathol 2003;6:6–23.
[Article] [PubMed]

21. Kliegman RM, Stanton B, St. Geme J, Schor N, Behrman RE. Nelson textbook of pediatrics. 2011;19th ed. Philadelphia: Elsevier Saunders, :601–603.

22. Lee JS, Polin RA. Treatment and prevention of necrotizing enterocolitis. Semin Neonatol 2003;8:449–459.
[Article] [PubMed] [PMC]

23. Reynolds JD, Ahearn GS, Angelo M, Zhang J, Cobb F, Stamler JS. S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood. Proc Natl Acad Sci U S A 2007;104:17058–17062.
[Article] [PubMed] [PMC]

24. Simmonds A, LaGamma EF. Addressing the "New" NEC: Part I: rediscovering the basics. Indian J Pediatr 2006;73:1011–1018.
[Article] [PubMed]

Table 1

Comparison of patient characteristics of the NEC and control groups

Values are presented as mean±standard deviation or number (%).

NEC, necrotizing enterocolitis; NS, not significant; Apgar 1, Apgar (appearance, pulse, grimace, activity, and respiration) score at 1 minuite; Apgar 5, Apgar score at 5 minuites; DIC, disseminated intravascular coagulopathy; PDA, patent ductus arteriosus; RDS, respiratory difficulty syndrome; O₂ day, time on O₂; BPD, bronchopulmonary dysplasia; PROM, premature rupture of membrane; RBC(t), red blood cell transfusion.

^*No significant difference between the two groups.

Table 2

Relative Risk for NEC in the Univariate Logistic Regression

NEC, necrotizing enterocolitis; CI, confidence interval; Apgar 1, Apgar (appearance, pulse, grimace, activity, and respiration) score at 1 minuite; Apgar 5, Apgar score at 5 minuites; DIC, disseminated intravascular coagulopathy; NS, not significant; RBC(t), red blood cell transfusion.

^*No significant difference between the two groups.

Table 3

Relative Risk for NEC in the Multivariate Logistic Regression after Adjustment^*

NEC, necrotizing enterocolitis; CI, confidence interval; RBC(t), red blood cell transfusion.

^*Adjusted variables: gestational age, Apgar (appearance, pulse, grimace, activity, and respiration) score at 1 minute, patent ductus arteriosus, respiratory difficulty syndrome, premature rupture of membrane, disseminated intravascular coagulopathy, and death.