Journal of Perinatology (2008) 28, 556–560 r 2008 Nature Publishing Group All rights reserved. 0743-8346/08 $30 www.nature.com/jp ORIGINAL ARTICLE Necrotizing enterocolitis during the first week of life: a multicentered case–control and cohort comparison study

G Stout1,2, DK Lambert1,2, VL Baer1,2, PV Gordon3, E Henry1, SE Wiedmeier1,4,5, RA Stoddard1,6, CA Miner1,6, N Schmutz1,2, J Burnett1,5 and RD Christensen1,2 1Neonatology, Intermountain Healthcare, Ogden, UT, USA; 2McKay-Dee Hospital Center, Ogden, UT, USA; 3Division of Neonatology, Department of Pediatrics, University of Virginia Children’s Hospital, Charlottesville, VA, USA; 4Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA; 5Intermountain Medical Center, Murray, UT, USA and 6Utah Valley Regional Medical Center, Provo, UT, USA

None who were fed human milk exclusively developed early NEC. Twelve Objective: Necrotizing enterocolitis (NEC) is rare during the first week of of the twenty-one were fed (by gavage or bottle) amounts exceeding the life; most cases occur after 2 to 4 weeks. We hypothesized that when NEC upper limit of volumes taken by breastfed neonates. develops in the first week, certain predisposing factors and feeding practices are identifiable. To test this, we sought to identify every case of NEC Conclusion: We speculate that the prevalence of NEC during the first diagnosed during the first week within the Intermountain Healthcare system week could be reduced by identifying at-risk patients, feeding them during the most recent 6-year period. human milk exclusively for the first week and using feeding volumes that do not exceed that taken by healthy breastfed neonates. Study Design: Data were collected from neonates admitted to any Journal of Perinatology (2008) 556–560; doi:10.1038/jp.2008.36; Intermountain Healthcare neonatal intensive care unit (NICU) with a 28, published online 27 March 2008 date of birth from 1 January 2001 through 31 December 2006. Electronic and paper records were obtained for all with a diagnosis of NEC (Bell Keywords: NEC; early NEC; feeding; human milk; formula; risk factors stage XII) within the first 168 h. X-rays, physician notes, nursing records, laboratory reports and operative reports were subjected to critical review to reexamine the diagnosis of NEC. Among those with confirmed NEC, we recorded underlying conditions and every feeding given prior to Introduction the diagnosis of NEC. Comparisons were made with patients that did not The prevalence of necrotizing enterocolitis (NEC) has 1 develop NEC, yet were cared for in the same NICUs, during the same not decreased appreciably during the past four decades. period of time, and of the same gestational ages. In part, this is explained by the capability of modern neonatology to sustain ever-smaller and more immature neonates, since Result: A total of 28 neonates were identified electronically as having NEC is more common among these patients.2 However, in part, NEC during the first week. Critical review confirmed this in 21, but 5 were this failure is due to the lack of successful NEC prevention determined at laparotomy to have had spontaneous intestinal perforation, strategies.3 and 2 others were found on surgical reports to have had a congenital Perhaps one reason prevention strategies have not been infarction of the colon. Total 20 of the 21 confirmed cases developed NEC particularly successful is that NEC is a multifactorial disease. while in a NICU being treated for another condition. The exception was a Consequently, no single approach to prevention is likely to pertain small-for-gestational-age neonate in a well baby nursery. Compared to to all subtypes.3,4 To focus our efforts on a small and potentially 6100 controls, the 21 with early NEC were more likely to have had a more homogeneous subtype of NEC, we conducted the present meconium-positive test for illicit drug exposure (P<0.005), early onset study of NEC occurring in the week following delivery. Using the sepsis (P<0.034) and respiratory distress (P<0.039). They were less data sets of Intermountain Healthcare, a healthcare delivery system likely than case–controls to have been fed human milk (P 0.003) ¼ in the western United States, we identified all patients in the past 6 and were more likely to have been fed formula exclusively (P 0.019). ¼ years with Bell stage XII NEC diagnosed during the first week. We examined the data from each case, and sought potential Correspondence: Dr RD Christensen, Neonatology, Intermountain Health Care, 4301 features and feeding practices that differed between these patients Harrison Blvd, Ogden, UT 84403, USA. compared with others who did not develop NEC yet were cared for E-mail: [email protected] Received 12 November 2007; revised 8 February 2008; accepted 14 February 2008; published in the same hospitals, at the same time, and were of the same online 27 March 2008 gestational ages. Early NEC G Stout et al 557

Methods Descriptive statistics were calculated using SPSS (v 13.0) for Windows. Between-group means were tested using independent Data were collected as a de-identified limited data set from archived samples t-tests when parametric assumptions were met, and with Intermountain Healthcare records. The information collected was Wilcoxon rank-sum tests used for nonparametric comparisons. limited to the information displayed in the Results section of this Proportions were compared between groups using the Fisher’s exact report. Data were obtained for patients admitted to any test. Two-tailed tests were used and for all tests a was set at 0.05. Intermountain Healthcare hospital with the diagnosis of NEC, Bell stage XII, during the first week (168 h) after birth. Data were limited to those with a date of birth between 1 January 2001 and 31 Results December 2006. A total of 28 neonates were identified, using the electronic medical When NEC was identified from electronic records, the medical records, as having NEC, Bell stage XII, with the diagnosis made records (paper charts) were examined by two or more of the within 168 h of birth. Critical review confirmed this diagnosis in 21 authors. All radiographic images, radiographic reports, physician’s of the 28. Five had pneumoperitoneum but no radiographic notes and nursing notes pertinent to the issue of NEC were evidence of pneumatosis or portal air. All five cases had a reviewed. To document the occurrence of NEC, we used the criteria laparotomy, with operative and pathological reports describing an originally proposed by Bell et al.,5 as subsequently modified isolated perforation in the distal small bowel without NEC. Thus, by Walsh and Kliegman,6 and adopted by the Vermont Oxford these five were recategorized as having SIP, not NEC. Two other Network.7 This definition required the presence of one or more infants with congenital cardiac defects, one with hypoplastic right of the following three clinical signs; (1) bilious gastric aspirate or heart syndrome, and the other with tricuspid atresia, had emesis, (2) abdominal distension, (3) occult or gross blood in stool pneumatosis intestinalis diagnosed on the second or third day. A (no fissure) and one or more of the following three radiographic laparotomy was performed immediately on both, and the operative findings; (1) pneumatosis intestinalis, (2) hepatobiliary gas, and pathological reports identified these as congenital ischemic (3) pneumoperitoneum. If a patient had focal gastrointestinal necrosis of the colon. perforation, based on visual inspection of the bowel at the time Two of the twenty-one with confirmed NEC were term infants. of surgery, the condition was not listed as NEC but as spontaneous These 2 cases were previously published among 30 cases of NEC in intestinal perforation (SIP). We note that while our methods of term infants.9 Total 20 of the 21 with confirmed NEC had been distinguishing NEC from SIP are not fully consistent with the admitted to a neonatal intensive care unit (NICU) for treatment of guidelines recently proposed by Gordon et al.,8 who pointed out that another condition. The other patient, a small-for-gestational-age pneumoperitoneum without pneumatosis would be categorized as NEC (SGA) infant with a tight nuchal cord at delivery, developed NEC if treated by abdominal drainage under the Vermont Oxford Network while in a well baby nursery. definitions, all infants with pneumoperitoneum receive laparotomy Clinical features of the 21 neonates who developed NEC and the within our system, thereby circumventing this diagnostic pitfall. 6100 who did not are listed in Table 1. Those who developed NEC The program used for data collection was a modified subsystem were more likely to have had a meconium-positive test for illicit of ‘clinical workstation’. 3M company (Minneapolis, MN) approved drugs, early onset bacterial sepsis and respiratory distress syndrome. the structure and definitions of all data points for use within the The specific drugs detected in meconium in the four cases were program. Data were collected from the electronic medical record, opiates (two cases), cocaine (one case) and cannabinoids case mix, pharmacy and laboratory systems. Trained and (one case). designated personnel entered and accessed data. The enteral Feeding practices among the 21 neonates who developed NEC feeding type (human milk vs formula) and the feeding method are shown in Table 3. Although the intent was to study 210 (breast vs bottle vs gavage) were not recorded in the electronic case–controls, 215 were actually studied. When compared with the record. Therefore, to obtain this information a case–control case–controls, those who developed NEC were less likely to have substudy was undertaken. For each confirmed case of NEC received human milk exclusively. In fact none of the neonates who (n ¼ 21), 10 controls were selected (n ¼ 210). The controls were developed NEC were fed human milk exclusively and they were matched with the cases on three elements; (1) they were selected more likely to have been fed formula exclusively (Table 2). from the same hospital, (2) they were of the same gestational age The volume of enteral feedings given to each patient before NEC (±1 week) and (3) they were selected from the same period of was diagnosed is shown in the Figure 1. Also shown on the figure is time (±3 months). Feeding volumes from breastfed neonates were the range of feeding volumes taken by healthy breastfeeding term estimated based on weighing them immediately before and after infants and by healthy bottlefeeding term infants during the first 2 breastfeeding (using a conversion of 1 g of weight gain ¼ 1mlof days after birth.10,11 At least 12 of the patients that developed NEC milk). The Intermountain Healthcare Institutional Review Board were fed volumes exceeding the upper limit of milk intake by approved the study. breastfeeding infants.

Journal of Perinatology Early NEC G Stout et al 558

Table 1 Clinical features (mean±s.d. or %) of 21 neonates with NEC diagnosed during the first 7 days after birth

Features Developed NEC in the Did not develop P-value first week (n ¼ 21) NEC (n ¼ 6100)

Maternal illicit drugs (%)a 19 (4) 3 (213) 0.005 Early onset sepsis (with positive blood culture) (%) 10 (2) 1 (88) 0.034 Respiratory distress syndromeb (%) 71 (15) 50 (3047) 0.039 Congenital heart diseasec (%) 5 (1) 0.4 (27) 0.088 Polycythemiad (%) 5 (1) 0.5 (31) 0.090 Maternal cigarette smokinge (%) 19 (4) 10 (620) 0.104 Race (% non-white) 24 (5) 16 (976) 0.138 Multiple birth (twin/triplet/quadruplet) 14 (3) 23 (1293) 0.174 Shock/hypotension/vasopressors (%) 14 (3) 12 (708) 0.226 Birth weight (g) 2257±627 2381±626 0.244 Apgar score @ 1 m 6.1±2.8 7.0±2.0 0.316 Gender (male) (%) 53 (11) 57 (3477) 0.415 C/S delivery (%) 53 (11) 48 (2925) 0.425 Gestational age (weeks) 34.4±3.1 34.6±2.0 >0.500 Apgar score @ 5 m 8.2±1.0 8.0±1.2 >0.500

Abbreviations: C/S; cesarean section; NEC, necrotizing enterocolitis. Compared with 6100 neonates that did not develop NEC (but were of the same gestational age range, cared for in the same NICUs and from the same period of time). The features were obtained from the electronic medical record and are listed in order of ascending P-value. aDetection of amphetamines, opiates, cannabinoids, cocaine or phencyclidine from neonate’s urine or meconium. b PaO2 <50 mm Hg in room air, central cyanosis in room air or a requirement for supplemental O2 to maintain PaO2 >50 mm Hg, and a chest radiograph consistent with RDS. cOther than patient ductus arteriosus. dHematocrit X70% or hemoglobin >23 g per 100 ml. eAs reported in prenatal records.

Table 2 Feeding practices are compared between two groups; 21 who developed NEC, Bell stage XII, during the first 7 days following birth vs 215 matched controls

N NPO Human Formula only Mixture of human Gavage feedings milk only milk and formula

Developed NEC 21 0 0 38% (8) 62% (13) 86% (18) Did not develop NEC 215 1% (3) 25% (54) 17% (37) 56% (121) 86% (185) P-value 0.755 0.003 0.019 0.399 0.588

Abbreviations: NEC, necrotizing enterocolitis; NPO, no enteral intake. Gavage feedings, any orogastric or nasogastric feedings given. The controls (10 controls for every one case of NEC) were matched with cases on the basis of gestational age, hospital of origin and period of time. Among the 21 who developed NEC, all feedings were tabulated between birth and the time NEC was diagnosed. Among the 215 controls, feedings were tabulated between birth and 168 h (7 days) of age.

Outcomes of those who developed early NEC are listed in 13 cases had either respiratory distress or polycythemia before NEC Table 3. Eight were transported to a regional children’s hospital for occurred. Eleven of the thirteen were fed before NEC developed, but surgical management. Five of these underwent abdominal surgery, it is not clear whether the two who were never fed had what today none had placement of a peritoneal drain. Of the five surgical we would define as NEC, or rather had another condition such as cases, one had extensive bowel resection and later died of sepsis, SIP13–15 or congenital infarction of the colon.15 In that report, and another had total bowel necrosis and support was withdrawn. Thilo et al.12 suggested that to reduce early cases of NEC, feedings These were the only two deaths (10% mortality rate); the other 19 were should be given more cautiously to neonates who had respiratory discharged to home following a hospital stay of 33.3±13.5 days. distress or polycythemia. It is possible that early NEC differs in fundamental ways from the classical variety that develops later. For instance, early NEC Discussion occurs almost exclusively in neonates born at >31 weeks’ Early NEC was described more than 20 years ago by Thilo et al.,12 gestation. Perhaps this is because those of higher gestation are who reported 13 cases from Children’s Hospital of Denver. All the more likely to receive substantial feedings during their first week,

Journal of Perinatology Early NEC G Stout et al 559

160

140

120 110.2

100 84.8 80 64.7 60 54.7

38.5 40 32.2 Feeding Volumes (mL/k) Feeding Volumes

18.5 20 13.3 13.0 9.6

0 123456 Day of Life

Infants with early NEC Breast Fed Controls Bottle Fed Controls

Figure 1 Daily enteral intake (feeding volume expressed in ml kgÀ1 birth weight), during the first week of life, among 21 patients that developed NEC during their first 7 days. Only the feedings preceding the diagnosis of NEC are shown. For comparison (gray bars) are shown the feeding volumes taken by healthy breastfed term neonates during the first 2 days following delivery (data obtained by weighing neonates before and after each breastfeeding).10,11 Also for comparison (white bars) are shown the feeding volumes taken by healthy bottlefed term neonates during the first 2 days following delivery.11

Table 3 Features and outcomes of 21 neonates who had NEC diagnosed during differentiate between those who were at risk for developing early the first 7 days following birth NEC from those who were not. The only predictive features we Feature Mean±s.d.; or found were the presence of maternal drug abuse, early onset (median; range);or infection, respiratory distress, exclusive artificial formula feeding (%) and perhaps feeding volumes in excess of what ‘nature’ may have intended. Age (days) when NEC was diagnosed 4.7±2.0 We recently reported on another relatively rare subtype of NEC, Was patient in the NICU being treated for another Yes (20) No (1) namely cases developing among term infants.9 The 30 cases in that condition? report, and the 21 cases in the present report, have several items in Transferred to children’s hospital for surgical 38% (8) management common. Actually, 2 of the cases of NEC in term neonates are Surgery for NEC 24% (5) included among the present 21 with early NEC, and therefore the Bowel resection 10% (2)a total of the two reports is 49 distinct cases. Taken together, 48 of Total bowel necrosis 5% (1)a the 49 had been admitted to a NICU for treatment before NEC Survived to discharge home 90% (19) developed. The only exception was in a well baby nursery and was Length of hospital stay for survivors (days) 33.3±13.5 SGA with the history of a tight nuchal cord. We speculate that the aPatients died (n ¼ 2). underlying conditions of the 49 resulted in a common pathophysiology involving aberrant mesenteric blood flow. Whether whereas those of earliest gestations are likely to receive fewer early this pathophysiology is transient or more chronic likely depends feedings. This association is one of many links between feeding upon the underlying disorder associated with each precondition and NEC pathogenesis.2–4 and may provide an explanation for disparate timing of NEC Other differences are apparent between patients who develop presentations between the two populations (early NEC vs term early NEC vs classical NEC. For instance, Guthrie et al.16 examined NEC). One example of a very transient precondition might be the patients with classical NEC vs controls who did not develop NEC, effects of illicit maternal drug use. A maternal illicit drug history and found them to be more likely to be delivered vaginally, was not observed as a common feature among term infants with with lower 5-min Apgar scores, and with lower birth weights. NEC,9 but was significant among those who developed early NEC. In contrast, in our present series of early NEC, compared with We observed marked similarities in the feeding practices used in controls, the mode of delivery, 5-min Apgar score, and birth these 49 patients (term NEC and early NEC). Specifically, none weights were similar. In fact, we found little to prospectively were fed with human milk exclusively, yet exclusive human milk

Journal of Perinatology Early NEC G Stout et al 560 feeding was quite common among the case–controls. Also, 3 Grave GD, Nelson SA, Walker WA, Moss RL, Dvorak B, Hamilton FA et al. New therapies exclusive formula feeding was significantly overrepresented among and preventive approaches for necrotizing enterocolitis: report of a research planning those who went on to develop NEC, while it was far less common workshop. Pediatr Res 2007; 62: 510–514. among the controls. 4 Gordon PV. The little database that could: Intermountain Healthcare and the uphill quest for prevention of term necrotizing enterocolitis. J Perinatol 2007; 27: 397–398. The mortality rate was also similar among the 21 patients with 5 Bell MJ, Shackelford P, Feigin RD, Ternberg JL, Brotherton T. Epidemiologic and 9 early NEC (10%) and the 30 term neonates with NEC (13%). In bacteriologic evaluation of neonatal necrotizing enterocolitis. J Pediat Surg 1997; 14: fact, the mortality rate we recently reported among 131 neonates 1–4. with NEC,17 most of which were classical cases, not early and not 6 Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. term neonates, was 6%. Statistically, there is no difference in Pediatr Clin North Am 1986; 33: 179–202. 7 Vermont Oxford Network Database. Manual of Operations, Release 10.0. mortality rate among these various groups of NEC patients. Burlington, VT, 2005, pp 77, 78. We speculate one reason NEC remains a largely enigmatic 8 Gordon PV, Swanson JR, Attridge JT, Clark R. Emerging trends in acquired neonatal condition is that it is actually several different entities. SIP is an intestinal disease: is it time to abandon Bell’s criteria? J Perinatol 2007; 27: 661–671. example of a condition sometimes confused with NEC.13–15 9 Lambert DK, Christensen RD, Henry E, Besner GE, Baer VL, Wiedmeier SE et al. Human milk feeding programs are not likely to reduce the Necrotizing enterocolitis in term neonates: data from a multihospital healthcare prevalence of SIP, since many or most cases of SIP occur before the system. J Perinatol 2007; 27: 437–443. 4 10 Dollberg S, Lahav S, Minouni FB. A comparison of intakes of breast-fed and bottle-fed first feeding. Similarly, viral gastroenteritis might be an entity distinct infants during the first two days of life. J Am Coll Nutr 2001; 20: 209–211. 4 from classical NEC. This illness might also be refractory to prevention 11 Evans KC, Evans RG, Royal R, Esterman AJ, James SL. Effect of caesarean section on using human milk. Thus, we maintain that as NEC prevention breast milk transfer to the normal term newborn over the first week of life. Arch Dis schemes are tested,3 it will be useful to attempt to categorize the NEC Child Fetal Neonatal Ed 2003; 88: F380–F382. cases into component entities. The present data and that in our 12 Thilo EH, Lazarte RA, Hernandez JA. Necrotizing enterocolitis in the first 24 h of life. 9 Pediatrics 1984; 73: 476–480. previous report lead us to conclude that term and early NECs are 13 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal pathogenically similar. Finally, we speculate that the prevalence of perforation using a national data set (1): SIP is associated with early indomethacin early NEC will fall if clinicians will systematically identify at-risk exposure. J Perinatol 2006; 26: 93–99. neonates in their NICU and then institute human milk feedings 14 Attridge JT, Clark R, Walker MW, Gordon PV. New insights into spontaneous intestinal (mother’s own milk or banked human milk) in conjunction with perforation using a national data set (2): two populations of patients with perforations. conservative feeding guidelines for the first week of life. J Perinatol 2006; 26: 185–188. 15 Attridge JT, Clark R, Gordon PV. New insights into spontaneous intestinal perforation using a national data set (3): antenatal steroids have no adverse association with References spontaneous intestinal perforation. J Perinatol 2006; 26: 667–670. 16 Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. 1 Moss RL, Dimmitt RA, Barnhart DC, Sylvester KG, Brown RL, Powell DM et al. Necrotizing enterocolitis among neonates in the United States. J Perinatol 2003; 23: Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N 278–285. Engl J Med 2006; 354: 2225–2234. 17 Wiedmeier SE, Henry E, Baer VL, Stoddard RA, Eggert LD, Lambert DK et al. Center 2 Neu J. Neonatal necrotizing enterocolitis: an update. Acta Paediatr Suppl 2005; 94: differences in NEC within one healthcare system may depend on feeding protocol. 100–105. Am J Perinatol 2008; 25: 5–12.

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