Published online December 4, 2006
PEDIATRICS Vol. 119 No. 1 January 2007, pp. e164-e170 (doi:10.1542/peds.2006-0521)
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ARTICLE

Prevention of Necrotizing Enterocolitis in Preterm Infants: A 20-Year Experience

Jeff Pietz, MDa,b, Babu Achanti, MDa,b, Lawrence Lilien, MDc, Erin Clifford Stepka, MD, PhDa,b and Sudhir Ken Mehta, MD, MBAa

a Neonatal Division, Department of Pediatrics, Fairview Hospital, Cleveland Clinic Health System, Cleveland, Ohio
b Pediatrix Medical Group, Cleveland, Ohio
c Department of Pediatrics, St Joseph Hospital, Phoenix, Arizona


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Diet, indomethacin, and early use of dexamethasone have been implicated as possible causes of necrotizing enterocolitis and intestinal perforation. Because we seldom prescribe indomethacin or early dexamethasone therapy and we follow a special dietary regimen that provides late-onset, slow, continuous drip enteral feeding, we reviewed our 20 years of experience for the incidence of necrotizing enterocolitis and bowel perforation.

METHODS. We reviewed data on all 1239 very low birth weight infants (501–1500 g) admitted to our level III unit over a period of 20 years (1986–2005), for morphologic parameters, necrotizing enterocolitis, bowel perforation, use of the late-onset, slow, continuous drip protocol, and indomethacin therapy. Outcome data were also compared with Vermont Oxford Network data for the last 4 years.

RESULTS. In 20 years, 1158 infants received the late-onset, slow, continuous drip feeding protocol (group I), whereas 81 infants had either a change in dietary regimen, use of indomethacin, or early use of dexamethasone (group II). The rate of necrotizing enterocolitis in group I of 0.4% was significantly lower than that in group II of 6%. Group I, in comparison with the Vermont Oxford Network, had significantly lower rates of necrotizing enterocolitis (0.4% vs 5.9%), surgical necrotizing enterocolitis (0.4% vs 3.1%), and bowel perforation (0.35% vs 2.2%).

CONCLUSIONS. Our 20-year experience with 1239 very low birth weight infants suggests strongly that the late-onset, slow, continuous drip feeding protocol and avoidance of indomethacin and early dexamethasone treatment contribute to the prevention of necrotizing enterocolitis.

Key Words: feeding • diet • very low birth weight infants

Abbreviations: NEC—necrotizing enterocolitis • LOSD—late-onset, slow, continuous drip • ELBW—extremely low birth weight • VLBW—very low birth weight

Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in newborn infants.1 NEC and intestinal perforation in very low birth weight (VLBW) infants are common emergencies that carry high mortality and morbidity rates. Among all NICU admissions, the incidence of NEC ranges from 1% to 7.7%, with 90% of cases occurring among premature infants.2 The incidence of NEC among VLBW infants is 10.1%, and NEC carries a mortality rate of 54% among infants with stage III disease.3 The postoperative morbidity rate is also high (47%), with the most common morbidities being sepsis (9%), intestinal strictures (9%), short gut (9%), wound infections (6%), and intraabdominal abscess formation (2.3%).4

The exact cause of NEC is unknown. On the basis of epidemiologic studies, prematurity and feeding with nonhuman milk are consistent known precursors of NEC.5,6 Microbial colonization, metabolic factors, and endocrine factors related to preterm birth after exposure to milk may make the immature intestine sensitive to atrophy and the development of NEC.7 The rate of administration of feedings may also influence the incidence of NEC.8,9 In the absence of accepted standards for feeding extremely low birth weight (ELBW) and VLBW infants, determining the precise effect of feeding on NEC is very challenging. The plausible association of indomethacin and NEC has been difficult to elucidate, which may be related to the fact that most studies do not account for feeding schedules as a confounder.

ELBW infants with spontaneous intestinal perforation have a significantly higher incidence of periventricular leukomalacia and death. It is a multifactorial disease, with an estimated incidence of 8.4% in ELBW infants.10 In ELBW infants, it is associated with simultaneous use of steroids and early indomethacin treatment.11 Intestinal perforation was also reported for ELBW infants who were exposed to indomethacin and had high endogenous cortisol levels.12 In therapeutic doses, indomethacin used for closure of patent ductus arteriosus may lead to a prolonged decrease in mesenteric blood flow.13 Although in earlier reports indomethacin was a co-risk factor with glucocorticoids for bowel perforation, a recent analysis of a national data set supported the early use of indomethacin as an independent risk factor for spontaneous bowel perforation.14

Our team of neonatologists has been impressed by the lack of evidence in published studies documenting benefits of indomethacin for preterm infants. This is particularly true for prophylactic indomethacin therapy. Our impression has been supported by large-scale studies.15,16 Even the need to close a patent ductus arteriosus has been questioned.17 As a result, over a period of 20 years, generally our preterm infants were not exposed to indomethacin or early dexamethasone treatment. In addition, our feeding protocol differs from the published protocols; it provides late-onset, slow, continuous drip (LOSD) enteral feeding.

The purpose of this study was to examine the prevalence of bowel perforation and NEC in a population of preterm infants who generally were not exposed to indomethacin therapy. In addition, the infants were on a strict feeding protocol designed to offer LOSD enteral feeding. Because the lack of indomethacin therapy and the use of strict feeding protocols may influence other outcome measures, we also present our recent key morbidity rates, compared with the Vermont Oxford Network database.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We reviewed the birth weights, use of indomethacin and early dexamethasone treatment, use of the LOSD feeding protocol, and specific outcomes for NEC, surgical NEC, bowel perforation, and short-gut syndrome among all 1239 VLBW infants (501–1500 g) who were admitted to our level III NICU between January 1, 1986, and December 31, 2005. The diagnosis of NEC was made on the basis of the criteria described by Bell et al.18 The charts were identified from the NICU admission logs, which were maintained meticulously for all infants at the time of admission. The logs include demographic data and discharge diagnoses. After review of the charts, data were entered into a spreadsheet with the aforementioned parameters. Because we enrolled in the Vermont Oxford Network in 2002, we reviewed our outcome data for a period of 4 years (January 1, 2002, to December 31, 2005), for length of stay, discharge weights, death, bronchopulmonary dysplasia, intraventricular hemorrhage (grades III and IV), nosocomial infections, and ligation of patent ductus arteriosus. The precise definitions of these outcome measures were the same as the definitions described in the Vermont Oxford Network annual report for 2004 (Vermont Oxford Network, written communication, 2004).

The general guidelines and details of our LOSD feeding protocol, which was instituted in 1986, are described in the Appendix. The protocol includes placing an umbilical artery catheter in infants with birth weights of <1200 g, to be replaced by a percutaneous intravenous catheter line at 5 days to 7 days. The percutaneous catheter lines were used until infants achieved adequate enteral intake to support hydration (>100 mL/kg per day). The placement of an umbilical catheter was not considered a contraindication for feeding.


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  		APPENDIX Feeding Protocol

 
The data are presented descriptively as raw mean ± SD values and percentages. Group differences regarding the prevalence of NEC and bowel perforation (groups I and II) and the incidence of bowel perforation, NEC, and other key outcome measures in our unit (2002–2005) and the Vermont Oxford Network (2002–2004) were tested with {chi}2 analysis with the Yates correction (2-tailed). Statistical significance was defined a priori as P < .05. The study was approved by the institutional review board of Fairview Hospital.


   RESULTS
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 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the period of 20 years (1986–2005), there were 1239 VLBW infants (501–1500 g), including 213 infants with birth weights of 501 to 750 g. Their birth weight and gestational age were 1061 ± 279 g and 28.3 ± 2.9 weeks, respectively, with male and female proportions of 51% and 49%. The proportions of white, black, and other infants were 75%, 16%, and 9%, respectively. The incidence of NEC among black, white, and other infants was 2.5% (5 of 201 infants), 0.5% (5 of 925 infants), and 0% (0 of 113 infants), respectively. The incidence of small-forgestational age status was 14% (173 of 1239 infants). During this period, there were 86 transports to the unit, whereas 30 infants were transported out, mostly for lower-level care. Among 1239 infants, 1158 received the LOSD feeding protocol with no indomethacin and no early dexamethasone treatment (group I). Eighty-one infants belonged to group II, in which 22 infants received indomethacin, 48 infants received early dexamethasone treatment, 10 infants received a different feeding protocol (2 of those infants received indomethacin and 1 infant received early dexamethasone treatment as well), and 1 infant received indomethacin and dexamethasone at day 2 of life. The incidences of NEC and bowel perforation among the infants are shown in Table 1. There were no infants with short-gut syndrome. Table 1 also includes a comparison of our 20-year data with the recent 3 years of data from the Vermont Oxford Network.


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  		TABLE 1 Incidence of NEC and Bowel Perforation in Infants With Birth Weights of 501 to 1500 g Who Received the LOSD Feeding Protocol, No Indomethacin, and No Early Dexamethasone Treatment (Group I) and Infants Who Received a Non-LOSD Feeding Protocol, Indomethacin, or Early Dexamethasone Exposure (Group II)

 
The demographic data and incidences of NEC, bowel perforation, and other key outcome variables for our NICU from January 2002 to December 2005 and for the Vermont Oxford Network during the period of January 2002 to December 2004 (at the time of this writing, 2005 data were not available) are shown in Tables 2 and 3. During those 4 years, the mean lengths of stay for our NICU and the Vermont Oxford Network were 54.6 days and 61.4 days, respectively; the mean discharge weights were 1925 g and 2368 g, respectively. Among the 18.6% of infants who had nosocomial infections, 56% of cases were attributable to coagulase-negative Staphylococcus. Among infants born with birth weights between 501 g and 750 g, our unit, compared with the Vermont Oxford Network (2002–2004), had significantly lower rates of NEC (1.9%, 4 of 213 infants, compared with 10.2%, 1988 of 19386 infants; P < .001) and bowel perforation (1.4%, 3 of 213 infants, compared with 5%, 1303 of 26085 infants; P < .025) for the same weight group over the period of 20 years.


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  		TABLE 2 Demographic Data for 4 Years (2002–2005) for Our NICU and the Vermont Oxford Network (2002–2004)

 

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  		TABLE 3 Key Outcome Variables for 4 Years (2002–2005) for Our NICU and the Vermont Oxford Network (2002–2004)

 
The salient clinical features of all 10 cases of NEC (0.8%, 10 of 1239 infants) in 20 years are shown in Table 4. None of these infants was small for gestational age.


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  		TABLE 4 Relevant Clinical Features of All 10 Cases of NEC Among 1239 Infants (0.8%) During 20 Years of Experience

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
The lower incidences of NEC and bowel perforation for our group I infants and similar or better overall key outcome variables, compared with the outcome variables reported for the Vermont Oxford Network, support our current practice of using the LOSD feeding protocol and abstaining from the use of indomethacin and early dexamethasone treatment. Although our findings do not support causal relationships between diet, early use of dexamethasone, and use of indomethacin and NEC, our data suggest strongly that the LOSD feeding protocol and the lack of indomethacin exposure contribute to the prevention of NEC and bowel perforation. Furthermore, our favorable outcome results were achieved without the liberal use of indomethacin.

On the basis of epidemiologic studies, non-Hispanic black infants have a higher incidence of NEC than do non-Hispanic white infants.19 Our results were similar (2.5% vs 0.5%); however, even among black infants, the rate of NEC in our unit was significantly lower than the reported incidence among infants of all races (5.9%) in the Vermont Oxford Network.

More than 90% of infants who develop NEC are seen after milk feeding. The feeding protocol that would be most suitable for preterm infants is not known, because of limited available information on protocol safety. Little information is available regarding NEC outcomes and early (<4 days) versus late (>4 days) initiation of feeding,20,21 minimal enteral feeding versus no enteral nutrient intake (no feeding or water intake only),22 or the rate of advancement of feeding.23 In a randomized trial of feeding advancement rates from 15 mL/kg per day to 35 mL/kg per day among 185 preterm infants, there was no difference in NEC rates (13% vs 9%).24 The clinical benefits and risks of continuous versus intermittent nasogastric tube milk feeding are also unclear.25 There is general agreement that fortified human milk protects against NEC and late-onset sepsis.26

Predisposition of VLBW infants to NEC may result from greater intestinal permeability, immature luminal function, and lower motility, leading to stasis, bacterial overgrowth, and bowel distention. The abnormal colonization of premature infants may contribute to the development of NEC. Clinical studies have supported the relationship of NEC with rapid advancement of enteral feedings and maximal gastric residuals.27,28 The LOSD feeding protocol not only offers cautious challenge to the immature intestine but also may offer total intestinal hygiene. The longer initiation time, smaller feedings than described in most clinical studies, and feedings given as a continuous drip, with judicious monitoring for residuals and abdominal distension, are key features of the LOSD feeding protocol. In addition to stool blood testing, possible intestinal distension secondary to constipation is prevented vigilantly by making sure that infants pass a stool daily. Deviation from the LOSD feeding protocol for 81 infants resulted in a 6% rate of NEC, 2.5% surgical NEC, and 2.5% intestinal perforation, rates that are similar to the average incidences reported by the Vermont Oxford Network (Vermont Oxford Network, written communication, 2004).

In <10% of cases, NEC occurs in infants without any enteric feeding. However, for physiologic and epidemiologic reasons, our outstanding results over a period of 20 years would be improbable through coincidence alone. Furthermore, the key to preventing NEC seems to be through the gastrointestinal tract (intake, output, changing the flora, or a combination thereof). For instance, probiotics fed enterally with breast milk reduced the incidence and severity of NEC in VLBW infants.29 A change in feeding practices alone resulted in a decreased incidence of NEC.30,31 By delaying the feeding initiation time, advancing feedings slowly, and opting for breast milk when possible, the NEC rate was decreased from 4.8% to 1.1% for infants at <35 weeks of gestation who weighed 1250 g to 2500 g.32 Our results were duplicated in Australia, where, with the adoption of a standardized feeding regimen in 1997, authors virtually eliminated NEC (only 1 case during a 5-year period among 78 infants at <28 weeks). Their diet included the use of erythromycin as a prokinetic and carboxymethylcellulose as a laxative, in addition to no enteral feedings if they used indomethacin for patent ductus arteriosus. Their feeding regimen was similar to other current practices.33 It is possible that our practice of regularly using glycerin suppositories (instead of carboxymethylcellulose) to ensure regular bowel movements, thus preventing intestinal distension, with its potential to alter intestinal blood flow,34 has a major role in our unit's favorable results. Erythromycin in lower doses as a prokinetic agent requires additional study before it can be recommended for routine use.35

Despite the lack of indomethacin use, our lower rate of surgical ligation of patent ductus arteriosus may be attributed to our practice of restricting medical treatment to symptomatic patent ductus arteriosus, with diuretics, fluid restriction to 130 to 150 mL/kg per day, and captopril to reduce systemic afterload. Oral water intake increases systemic vascular resistance in adults.36 By delaying feedings and avoiding gastric distention with the LOSD protocol, in theory keeping systemic vascular resistance low, we may be improving our infants' ability to tolerate a patent ductus arteriosus. Furthermore, the infants are maintained with high-frequency ventilation, volume-guarantee ventilation, and variable-flow continuous positive airway pressure if they experience pulmonary symptoms. Most patent ductus arteriosus ligations in our unit were performed for infants with birth weights of <750 g who were having difficulty maintaining adequate urine output despite optimal medical therapy.

The reason for our consistently low intraventricular hemorrhage rate without regular use of indomethacin is unclear. Perhaps it is related to our practice of not extubating tiny infants until after they are 72 hours of age; we are less aggressive in using nasal continuous positive airway pressure for these infants in their first few days of life. As pointed out in a recent study,37 the rates of intraventricular hemorrhage, bronchopulmonary dysplasia, and NEC may all have familial and genetic origins.

Because the use of indomethacin has been implicated in spontaneous bowel perforations, our delicate handling of and respect for the gastrointestinal tract and the lack of indomethacin and early dexamethasone use in combination might have contributed to our lower rate of intestinal morbidity. There may not be a single factor alone; perhaps the combination of the several aforementioned factors (and possibly some unknown factors) led to our outstanding NEC and bowel perforation rates. Feeding studies rarely address all aspects of the feeding of VLBW infants. In contrast, we have provided full details regarding the LOSD feeding protocol, with the hope of stimulating prospective studies in similar units that would help address this issue. Controlled trials are needed to elucidate the possible role of controlled feeding protocols, with or without indomethacin, and to determine the factors that may play important roles in the pathogenesis of NEC and bowel perforation.


   ACKNOWLEDGMENTS
 
We thank our team of perinatologists, pediatricians, and wonderful nursing staff members for supporting and caring for our unit; this work would not have been possible without their active cooperation. We thank Denise Betlejewski, RN, and her team for constant support and vigilant supervision. We are also grateful to Kim Brown for administrative assistance and to our incredible medical records department.


   FOOTNOTES
 
Accepted Jul 18, 2006.

Address correspondence to Jeff Pietz, MD, Neonatal Intensive Care Unit, Fairview Hospital, 18101 Lorain Ave, Cleveland, OH 44111-5656. E-mail: jeff_pietz{at}pediatrix.com

The authors have indicated they have no financial relationships relevant to this article to disclose.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2007 by the American Academy of Pediatrics




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