Necrotizing enterocolitis in term neonates - Nature

Journal of Perinatology (2007) 27, 437–443 r 2007 Nature Publishing Group All rights reserved. 0743-8346/07 $30 www.nature.com/jp

ORIGINAL ARTICLE

Necrotizing enterocolitis in term neonates: data from a multihospital health-care system DK Lambert1,2, RD Christensen1,2, E Henry1,3, GE Besner4, VL Baer1,2, SE Wiedmeier1,5,6, RA Stoddard1,7, CA Miner1,7 and J Burnett1,6 1

Intermountain Health Care, Ogden, UT, USA; 2Department of Neonatology, McKay-Dee Hospital Center, Ogden, UT, USA; 3The Institute for Healthcare Delivery Research, Salt Lake City, UT, USA; 4Department of Pediatric Surgery, Children’s Research Institute, Children’s Hospital, Columbus, OH, USA; 5Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA; 6 Department of Neonatology, LDS Hospital, Salt Lake City, UT, USA and 7Department of Neonatology, Utah Valley Regional Medical Center, Provo, UT, USA

Objective: In the past 5½ years, 30 term or near-term neonates in the Intermountain Healthcare system developed necrotizing enterocolitis (NEC) Bell’s stage XII. We sought to identify possible explanations for why these patients developed NEC, by comparing them with 5847 others that did not develop NEC, from the same hospitals and of the same gestational ages, cared for during the same 5½-year period.

Study design: Data were collected from neonates admitted to any of the Intermountain Healthcare NICUs with a birth date from 1 January 2001 to 30 June 2006, and a gestational age >36 weeks. A variety of patient features and feeding practices were compared between those that did vs did not develop NEC. Result: Forty-one neonates >36 weeks gestation were listed in the discharge records as having NEC of Bell’s stage II or higher. However, on review of these 41 medical records, 11 were seen to have had NEC of Bell’s stage I, whereas the remaining 30 had radiographs and clinical courses indicative of Bell’s stage XII. Those 30 formed the basis of this study. Twenty-eight of the 30 developed NEC after having been admitted to an NICU for some other reason; the other two developed NEC at home, within 2 days of being discharged from an NICU. The 30 that developed NEC were more likely than the 5847 that did not develop NEC, to have congenital heart disease (P ¼ 0.000), polycythemia (P ¼ 0.002), earlyonset bacterial sepsis (P ¼ 0.004) or hypotension (P ¼ 0.017). All 30 received enteral feedings before NEC developed; 29 were fed either artificial formula or a mixture of formula and breast milk. The one that was exclusively fed human milk was fed human milk with added fortifier (24 cal/oz). The 30 that developed NEC were more likely to be fed formula exclusively (P ¼ 0.000). Seven of the 30 had a laparotomy for NEC; two of the seven had total bowel necrosis and support was withdrawn. The

Correspondence: Dr RD Christensen, Intermountain Health Care, 4403 Harrison Blvd, Ogden, UT 84403, USA. E-mail: [email protected] Received 26 January 2007; revised 22 February 2007; accepted 25 February 2007; published online 29 March 2007

other five had perforations and bowel resections. The mortality rate was 13% (4/30). Conclusion: In our series, NEC among term or near-term neonates was exclusively a complication developing among patients already admitted to a NICU for some other reason. We speculate that the combination of reduced mesenteric perfusion and feeding with artificial formula were factors predisposing them to develop NEC. Journal of Perinatology (2007) 27, 437–443; doi:10.1038/sj.jp.7211738; published online 29 March 2007 Keywords: NEC; term infant; risk factors; human milk; congenital heart disease; NNT (number needed to treat)

Introduction Necrotizing enterocolitis (NEC) occurs primarily among prematurely delivered infants.1 However, rarely, NEC develops in full-term infants. In fact, since 1973, published reports have described over 150 term and near-term neonates with NEC.2–16 The prevalence of NEC among term neonates in the USA is not known, but Bolisetty et al.10 estimated that, in Australia, NEC occurs in one per 20 000 term births. As NEC is so rare among term neonates, it is challenging to develop and test prevention strategies. Intermountain Healthcare is a large health-care delivery system in the Western United States. We suspected that more cases of NEC in term infants would exist in the recent Intermountain Healthcare databases than in any of the published reports of this condition.2–16 Our speculation was based on the fact that all but one of the previous reports of NEC in term neonates10 were the experiences of individual hospitals. Thus, we undertook the present study, for two purposes; (1) to describe the cases of NEC of Bell’s stage XII in term neonates cared for in the Intermountain Healthcare NICU system in recent years and (2) to contrast data from these patients with data from term neonates admitted to the same NICUs that did

NEC in term infants DK Lambert et al

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not develop NEC. In this way, we sought associations between clinical features and feeding practices, and the development of NEC. Our overall purpose was to derive an evidence-based approach to reducing the incidence of NEC among term infants in our health-care system.

Materials and methods Data were collected as a deidentified limited data set from archived Intermountain Healthcare records. The information collected was limited to the information displayed in the results section of this report. Data were obtained for patients admitted to the NICUs at McKay-Dee Hospital, Ogden, UT, LDS Hospital, Salt Lake City, UT, Primary Children’s Medical Center, Salt Lake City, UT and Utah Valley Regional Medical Center, Provo, UT, with a date of birth from 1 January 2001 to 30 June 2006. We studied only patients delivered at >36 weeks gestation that had a diagnosis of NEC of Bell’s stage XII. When NEC was identified from electronic records, the medical records (paper charts) were examined by two or more of the authors. All radiographic reports, physician’s notes and nursing notes pertinent to the issue of NEC were reviewed. To document the occurrence of NEC, we used the criteria originally proposed by Bell et al.,17 as subsequently modified by Walsh and Kliegman,18 and adopted by the Vermont Oxford Network.19 This definition required the presence of one or more of the following three clinical signs; (1) bilious gastric aspirate or emesis, (2) abdominal distension, (3) occult or gross blood in stool (no fissure) and one or more of the following three radiographic findings; (1) pneumatosis intestinalis, (2) hepato-biliary gas and (3) pneumoperitoneum. If a patient had focal gastrointestinal perforation, based on visual inspection of the bowel at the time of surgery or post-mortem examination, the condition was not listed as NEC but as Focal Gastrointestinal Perforation and the patient was not considered as part of this study. The program used for data collection was a modified subsystem of ‘clinical workstation’. 3M Company (Minneapolis, MN) approved the structure and definitions of all data points for use within the program. Data were collected from the electronic medical record, case mix, pharmacy and laboratory systems. Trained and designated personnel enter and access data. The enteral feeding type (human milk vs formula) and method (breast vs bottle vs gavage) were not recorded in the electronic record. Therefore, to obtain this information, dietary records (paper) were reviewed for 430 patients, including the 30 that developed NEC plus 400 that did not develop NEC. The 400 records included 100 at McKay-Dee Hospital, 100 at LDS Hospital, 100 at Primary Children’s Medical Center and 100 at Utah Valley Regional Medical Center. The most recent 400 admissions in the study period, >36 weeks gestation, were selected for the review of feeding type and method. The Journal of Perinatology

Intermountain Healthcare Institutional Review Board approved the study. Descriptive statistics were calculated using SPSS (v 13.0) for Windows. Between-group means were tested using independent samples t-tests when parametric assumptions were met, and with Wilcoxon Rank-Sum tests used for non-parametric comparisons. Proportions were compared between groups using the Fisher exact test. Two-tailed tests were used, and for all tests a was set at 0.05.

Results The Intermountain Healthcare NICUs admitted 11 523 neonates with dates of birth of January 1, 2001 to June 30, 2006. Of these, 5877 (51%) were >36 weeks gestation at delivery. Of these, 41 were listed in the electronic records as having NEC Bell’s stage II or higher. We reviewed the medical records (paper charts) of each of these 41 and moved 11 from the ‘NEC group’ to the ‘No NEC group’, because no radiological evidence of pneumatosis, hepato-biliary gas or pneumatoperitoneum was found. Also, these Table 1 Clinical features of 30 term or near-term neonates that developed NEC vs 5847 others that did not develop NEC but were of the same gestational age range and were cared for in the same NICUs during the same period of time Features

Congenital heart diseasea Polycythemiab Early-onset bacterial sepsis Birth weight (g) Hypotension Endotracheal intubation PDA On vasopressors Maternal antenatal corticosteroids Meconium aspiration Maternal cigarette smoking Intrapartum antibiotics Non-white race Gestational age at birth (weeks) Apgar (1 min) Apgar (5 min) Gender (percent male) Maternal age (years)

Developed NEC Did not develop (n ¼ 30) NEC (n ¼ 5847) 27% (8) 7% (2) 13% (4) 2849±581 27% (8) 60% (18) 23% (7) 20% (6) 7% (2) 7% (2) 3% (1) 30% (9) 20% (6) 37.6±1.4 6.9±2.0 8.2±1.5 53% (16) 26.9±6.0

5% (270) 0.2% (13) 2% (131) 3180±594 12% (713) 41% (2395) 15% (867) 12% (724) 2% (137) 3% (151) 10% (564) 29% (1681) 17% (997) 38.2±1.4 6.7±2.2 8.1±1.5 59% (3438) 26.9±5.6

P-value*

0.000 0.002 0.004 0.010 0.017 0.028 0.081 0.090 0.125 0.141 0.153 0.156 0.165 NS NS NS NS NS

Abbreviations: NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; NS, not significant; PDA, patient ductus arteriosus. Features are listed in ascending order of P-value (comparing the group that did vs the group that did not go on to develop NEC). *P-values X0.200 are listed as ‘NS’, whereas values 70% or Hgb>23 g/dl.


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11 all had mild clinical courses with resumption of feedings within 3–5 days of onset of illness and with antibiotic use of fewer than 7 days. The remaining 30 all had confirmed Bell’s stage II or III NEC and were included in the study ‘NEC group’. Clinical features of the 30 patients that developed NEC, and the 5847 that did not, are contrasted in Table 1. Congenital heart disease was much more common among those that developed NEC, as was polycythemia, early-onset bacterial sepsis, hypotension and endotracheal intubation. The two patients with polycythemia that subsequently developed NEC both had a reduction transfusion performed through an umbilical venous catheter. Birth weights were lower among those that developed NEC. Eight of the 30 were small for gestational age (SGA, weight 36 weeks gestation, are shown in Table 2. The most common admitting diagnosis was respiratory distress; eight of 1929 with this admitting diagnosis subsequently developed NEC. Eight of 534 (1.5%) with a primary admitting diagnosis of suspected or proven congenital heart disease subsequently developed NEC. The specific diagnoses among the eight with congenital heart disease that subsequently develop NEC were pulmonary atresia (n ¼ 2), double outlet right ventricle

Table 2 Primary diagnoses on admission to the NICU of 5877 consecutive NICU admissions >36 weeks gestation, 30 of which went on to develop NEC and 5847 of which did not go on to develop NEC Primary diagnosis on admission to the NICU

Respiratory distress Suspected infection Suspected or proven congenital heart disease Hypoglycemia Gastroschisis-omphalo-TEF-imperforate anusa Aspiration Jaundice Transient tachypnea Seizures Birth depression Pulmonary hypertension Pneumothorax Shock/sepsis/metabolic acidosis Polycythemia Other

n

1929 1102 534 446 185 158 126 123 63 43 38 29 16 15 1070

Number that subsequently developed NEC (%) 8 (0.4%) 0 8 (1.5%) 0 0 0 0 0 0 4 (9%) 0 0 8 (50%) 2 (13%) 0

Abbreviations: NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit. a The primary reason for admission was listed as any of the following gastroschisis, omphalocele, tracheo-esophageal fistula or imperforate anus.

(n ¼ 2), tricuspid atresia (n ¼ 1), interrupted aortic arch (n ¼ 1), hypoplastic right heart (n ¼ 1) and tetralogy of Fallot (n ¼ 1). NEC developed among 9% of those with a primary admitting diagnosis of birth depression, among 50% of those with an admitting diagnosis of shock/sepsis and among 13% of those with an admitting diagnosis of polycythemia (Table 2). In contrast, NEC developed among none of those admitted to the NICU with the primary diagnosis of suspected infection, hypoglycemia, aspiration or jaundice. Similarly, NEC developed among none of 185 patients admitted with surgical conditions of the bowel (gastroschisis, omphalocele, tracheoesophageal fistula or imperforate anus) (Table 2). Features of the NEC that developed among the 30 patients are shown in Table 3. The majority, 28 of 30 were patients in a NICU being treated for some other underlying disorder, when the NEC developed. The two exceptions were both at home when NEC developed, but both had been discharged from a NICU 1 or 2 days earlier. Both had been admitted to a NICU immediately after birth, with respiratory distress. Then, at home, after a 4–6-day NICU stay, abdominal distention and bloody stools occurred, necessitating readmission for treatment of NEC, and subsequent transfer to Primary Children’s Medical Center for surgical management. The 30 that developed NEC were, on average, about 2 weeks old when NEC developed, but the range spanned from day 1 to 46 (Figure 1). Eight of the 30 patients with NEC were transferred to Primary Children’s Medical Center for surgical management (Table 3). Seven of the eight underwent laparotomy; five had perforations discovered and underwent bowel resections and two had total Table 3 Features of NEC among 30 term or near-term neonates Feature

Age (days) when NEC was diagnosed Location of patient when NEC developed Transferred to children’s hospital for surgical management Surgery for NEC Bowel perforation and resection Total bowel necrosis diagnosed Survival (%) Length of hospital stay (days) – all 30 patientsb Length of hospital stay (days) – 26 survivors

Mean±s.d.; or (median; range); or (%) 15±12; (12; 1–46) Home ¼ 2;a WBN ¼ 0; NICU ¼ 28 8 (27%) 7 (23%) 5 (17%) 2 (7%) 26/30 (87%) (32; 2–244) (37; 7–145)

Abbreviations: NEC, necrotizing enterocolitis (Bell’s stage II or III); NICU, neonatal intensive care unit; WBN, well baby nursery. a Two patients developed NEC at home, but both had been discharged from a NICU 1 day (first case) or 2 days (second case) before the NEC was recognized. Both cases had bloody stools and abdominal distention occurring at home, prompting hospital readmission. b Includes the four patients that died (on day of life 2, 7, 108 and 244). Journal of Perinatology


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intestinal necrosis discovered, and life-support was withdrawn later that day. Of the 30 with NEC, 26 lived and four died (Table 3). All four that died had been transferred to the children’s hospital for surgical management. Two were those where life-support was withdrawn for total bowel necrosis. Both of those had the initial diagnosis of polycythemia and both were fed formula only (no breast milk). They died on days 7 and 9, respectively. The third patient who died had extensive bowel resections and survived the surgery but died in the NICU on day of life 244 with chronic liver failure. The fourth non-survivor did not have surgery, but died in the children’s hospital NICU on day of life 108 with chronic liver failure. The enteral intake before NEC was diagnosed is described in Table 4, and is contrasted with the enteral intake during the first 14 days of life among 400 NICU patients that did not develop NEC but were of the same gestational age range, in the same NICUs, during the same period of time. No cases of NEC developed among neonates that were entirely breast-fed. The one patient that developed NEC and was fed only breast milk was fed expressed milk to which commercial fortifier (24 cal/oz) had been added. The majority (53%) of those that developed NEC had been fed

Number of NEC cases

12

Other SGA Polycythemia Cardiac

10 8 6 4 2 0 1-5

6-10

11-15

16-20

21-25

26-30

31-35

36-40

41-46

Days after birth

Figure 1 The day NEC was diagnosed among 30 term and near-term neonates. The 30 patients included eight with congenital heart disease, two with polycythemia, eight who were SGA and 12 others with the diagnoses of birth depression, respiratory distress or sepsis/shock.

exclusively with formula, whereas only 13% of those that did not develop NEC were fed exclusively with formula (P ¼ 0.000). Feeding by gavage was not more common among those that developed NEC than among those that did not develop NEC. Discussion NEC is the most common gastrointestinal emergency of preterm neonates,1 but since 1973, NEC has also been known to occur, albeit rarely, among term neonates.2 It is not clear whether NEC in term neonates is a fundamentally different disorder than NEC in preterm neonates, however, several authors have speculated that it is.7,8,10,11,15 One often-sited unique feature is that term infants who develop NEC generally have an underlying congenital condition or disease (Table 5). This was certainly the case among our 30 patients, each of which had previously been admitted to a NICU for some reason other than NEC, and subsequently developed NEC as a complication of care. We found no case where NEC developed in a completely well neonate. Rather, all had some antecedent illness requiring NICU admission. This association appears in the great majority of previously published cases of NEC among term infants.2–12,14–16 On the basis of the present and previous reports, we maintain that NEC in term neonates is a problem essentially limited to those that have some underlying illness or condition requiring NICU admission. If this is correct, the problem of preventing NEC in term infants may be less daunting than we initially anticipated. Specifically, if NEC in term infants is viewed as a condition occurring in one per 20 000 term neonates,10 prevention schemes would be exceedingly difficult to test because of the very large NNT (number needed to treat) to prevent one case. However, if NEC in term infants is viewed as a complication arising among those requiring NICU admission for certain disorders, targeted prevention schemes could be practical. One type of targeted prevention scheme could involve administering a potentially protective substance to at-risk neonates. For instance, heparin-binding epidermal growth factor

Table 4 Association between feedings and development of NEC in term or near term neonates

Developed NEC Did not develop NEC P-value

n

Fed human milk only

Fed formula only

Fed mixture

NPO for entire period a

Fed by gavage b

30 400

3% (1)c 27% (109) 0.001

53% (16) 13% (52) 0.000

43% (13) 54% (215) 0.082

0% (0) 6% (24) 0.168

63% (19) 60% (238) 0.363

Abbreviations: NPO, ‘nil per os’, or no enteral feedings; NEC, Necrotizing enterocolitis, Bell’s Stage II or higher; NICU, neonatal intensive care unit. Feeding information is shown for 30 neonates that developed NEC and for 400 that did not. The 430 patients were from the same NICUs, during the same period of time, and were of the same gestational ages. a The ‘period’ for the 30 that developed NEC was the time between birth and development of NEC (mean 15 days). The ‘period’ for the 400 that did not develop NEC was the first 14 days after birth. b If any feedings were given by OG or NG tube during the study period, ‘fed by gavage’ was recorded. c The one patient that was fed human milk exclusively and developed NEC was fed human milk fortified to 24 cal/oz using a commercial human milk fortifier. Journal of Perinatology

Table 5 Reported cases of NEC among term and near-term neonates Author/s

New cases reported (n)

1973 1976 1983 1983 1990 1997 2000 2000 2001 2004 2003 2007

Enteral intake before NEC (% yes)

Fed formula before NECb (% yes)

Predisposing factors identified (%)

Patient location when NEC developed (% in NICU)

Single Single Single Single Single Single Single Multiple Single Single

F F 95 F 100 91 100 F F 100

F F 68 F F 100 F F F 100

50 100 47 100 60 88 100 66 100 50

100 100 F F F F F 100 F F

7.1 (Range ¼ 6 h–5 days) 2 3.3 4.5 8.0 8.5 4.1

Single Multiple

F 100

F 97

62 100

F 100

5 15

Report period

Single vs multiple institution reporting

2 13 19 5 10 24a 4 29 16 14

F 20 years 17 months 2 years 5 years 4 years 2 months 6½ years 12 years 5 years

26 30

30 years 5½ years

Mean age of onset (days)

Day 17, day 1 c

Survival rate (%)

0 15 89 60 90 88 100 93 75 93


Rodin et al. Polin et al. de Gamarra et al. Goldberg et al. Andrews et al. Martinez-Tallo et al. Fatica et al. Bolisetty et al. Ruangtrakool et al. Maayan-Metzger et al. Ostlie et al. Present study

Year of publication

65 87

Abbreviations: NEC, necrotizing enterocolitis; NICU, neonatal intensive care unit; F, not reported. Publications contributing multiple (at least two) original cases are included. Reports of individual cases and review articles that did not contribute original cases are not included. a Patients were included if >2000 g birth weight, regardless of gestational age. b Percentage of those fed who were given formula or a mixture of formula and breast milk before NEC was diagnosed. c Four of five with congenital heart disease were affected within the first few days of life. Eight with pre-existing diarrhea had onset of NEC at an average of 26 days of life.

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(HB-EGF),20–22 EGF,23 other enteral growth factors24,25 or probiotics26,27 could be administered to term neonates that require NICU admission, using a randomized, placebo-controlled and masked design. Alternatively, if human milk was postulated to be protective, studies that randomized bottle-fed infants to banked human milk vs formula could be tested. Prophylactic studies in neonatology are inherently challenging, particularly when the disorder of interest is rare. One way to deal with this is to focus studies on subgroups at the highest risk for developing the unwanted outcome. For instance, McElhinney et al.11 observed that 7.6% of term neonates with hypoplastic left heart syndrome developed NEC. Using that figure, if HB-EGF administration prevented NEC among term neonates with hypoplastic left heart syndrome, the NNT would be only about 13 HB-EGF recipients per one case of NEC prevented. Thus, as accurate statistical estimates are made for the risk of NEC in various underlying conditions, and as plausible NEC prevention strategies like HB-EGF administration are identified, targeted prevention trials can be devised that do not require thousands of research subjects. Conditions besides functionally univenticular heart syndromes that increase the risk of NEC in term neonates include perinatal asphyxia,6,7,10,11,14 polycythemia,6,7 hypotension6,7,11,14 and early-onset bacterial infection.6,10,14 Perhaps, the common feature of these predisposing features is reduced mesenteric perfusion. McElhinney et al.11 came to this same conclusion when studying term neonates with congenital heart disease that developed NEC. They reported that patients with clinical shock had the highest odds of developing NEC and they ascribed this association to reduced mesenteric perfusion.11 Moreover, in an animal model of reduced mesenteric perfusion, NEC-like mucosal and submucosal injury occurs.28 We find it interesting and potentially important that in that animal model, the villous microvascular blood flow can be restored and the injury prevented by HB-EGF treatment.28 In our present series, we observed an association between formula feeding and the development of NEC. Reports by de Gamarra et al.,4 Andrews et al.,7 Martinez-Tallo et al.8 and Maayan-Metzger et al.15 mentioned that every term neonate that developed NEC, in their reports, had been fed before NEC developed. Martinez-Tallo et al.8 and Maayan-Metzger et al.15 reported that all had been fed artificial formula, not breast milk. In preterm neonates, a protective effect of human milk toward NEC was reported by Lucas and Cole29 and Schanler.30 Whether breastfeeding protects term neonates admitted to a NICU from NEC is not known, but such a speculation is supported by our present observations. In addition to the feeding substance used (breast milk vs various formulas), feeding plans can vary based on route of administration and rate of volume escalation. We found no association between the practice of gavage feeding and the development of NEC. We are uncertain about the rate of volume Journal of Perinatology

escalation and development of NEC. Of note, term neonates with gastroschisis are very rarely reported to develop NEC. In fact, among the 150 term neonates reported with NEC (Table 5), we can find only one that had gastroschisis. We speculate that the very slow and cautious escalation of feeding volumes generally provided patients with gastroschisis may help protect them from NEC. Contrariwise, perhaps more rapid escalation of feeding volumes among other at-risk, ill-term NICU patients, such as patients with congenital heart disease, polycythemia or early-onset shock, could be contributory to NEC. In recent reports, the mortality rate for patients with NEC is 6–20%.1,31 Obviously, the great majority of those are preterm infants. The mortality rate in our present series was 13% 4/30. This rate is within the range of other reports of NEC in term infants published this decade;11,12,14–16 of 0–35% (Table 5). Thus, it appears that the mortality rate for patients with NEC is similar whether they are preterm or term. Successful efforts are needed to prevent NEC among term neonates. It seems to us that such efforts can focus on the subgroups of term and near-term neonates that require admission to a NICU where their pathophysiology involves reduced mesenteric perfusion. Perhaps, reasonable starting places for prevention trials among such patients would include pharmacological prevention strategies, and human milk feeding programs.

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Clark JA, Doelle SM, Halpern MD, Saunders TA, Holubec H, Dvorak K et al. Intestinal barrier failure during experimental necrotizing enterocolitis: protective effect of EGF treatment. Am J Physiol Gastrointest Liver Physiol 2006; 291: G938–G949. Christensen RD, Havraneck T, Gerstmann DR, Calhoun DA. Enteral administration of a simulated amniotic fluid to very low birth weight neonates. J Perinatol 2005; 25: 380–385. Barney CK, Lambert DK, Alder SC, Scoffield SH, Schmutz N, Christensen RD. Treating feeding intolerance with an enteral solution patterned after human amniotic fluid: A randomized, controlled, masked, trial. J Perinatol 2007; 27: 28–31. Bin-Nun A, Bromiker R, Wilschanski M, Kaplan M, Rudensky B, Caplan M et al. Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates. J Pediatr 2005; 147: 192–196. Lin HC, Su BH, Chen AC, Lin TW, Tsai CH, Yeh TF et al. Oral probiotics reduce the incidence and severity of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2005; 115: 1–4. El-Assal O, Marquez A, Besner G. HB-EGF preserves mesenteric microcirculatory blood flow and protects against intestinal injury in rats subjected to hemorrhagic shock and resuscitation. 2007 (submitted for publication). Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519–1523. Schanler RJ. The use of human milk for premature infants. Pediatr Clin North Am 2001; 48: 207–219. Wiedmeier SE, Henry E, Baer VL, Stoddard RA, Lambert DK, Christensen RD. Necrotizing enterocolitis in three level III NICUs within one healthcare system. 2007 (submitted for publication).

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