NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #59
                           Carol Rees Parrish, R.D., M.S., Series Editor
                           Nutritional Management of the
                           Infant with Necrotizing Enterocolitis
                           Patti Perks                                      Ana Abad-Jorge
                           Necrotizing enterocolitis (NEC), an inflammatory gastrointestinal disease, occurs in
                           1%–5% of infants in neonatal intensive care units with a reported mortality rate of
                           25%–66%. Research efforts are directed at elucidating the cause and pathogenesis of
                           NEC in attempts to improve preventive as well as treatment measures. Current pre-
                           ventive strategies include: trophic feedings, standardized feeding regimens, provision of
                           breast milk, arginine supplementation, probiotic therapy, and infection control mea-
                           sures. Nutritional management with adequate parenteral nutrition and reintroduction
                           of enteral feeding, avoiding reoccurrence of NEC and minimizing complications, is
                           essential. The following article will present an overview of nutritional management of
                           NEC and related complications.
             INTRODUCTION                                                   are a variety of factors which contribute to its develop-
                   ecrotizing enterocolitis (NEC) is an inflamma-           ment and pathophysiology (2,4,5). While 90%–93% of
                   tory gastrointestinal (GI) disease process charac-       all infants who develop NEC are preterm, there have
            Nterized by tissue necrosis and, while commonly                 been no documented cases of intrauterine NEC, which
             seen in the neonatal intensive care unit (NICU), can           may be related to the sterility of the intrauterine GI
             also occur in critically ill term infants (1–3). The pre-      tract. The most recent data suggests that NEC affects
             cise etiology of NEC remains unclear; however, there           between 5%–10% of very low birth weight (VLBW)
                                                                            infants (<1500 grams), with the most susceptible
             Patti Perks, MS, RD, CNSD, NICU Nutrition Support              infants being the extremely low birth weight (ELBW)
             Specialist, UVA Health System, Department of Nutri-            infants, (<1000 grams) (1,6). Overall, NEC occurs in
             tion Services, Charlottesville, VA. Ana Abad-Jorge,            1%–5% of neonates admitted to the NICU, although
             MS, RD, CNSD, Director, Dietetic Internship Program,           the incidence of NEC has been found to be unit depen-
             Pediatric Nutrition Support Specialist, UVA Health             dent. The overall mortality of NEC is 25%, but has
             System, Department of Nutrition Services,Char-                 been reported as high as 66% in VLBW infants (7). In
             lottesville, VA.                                                                                  (continued on page 48)
             46    PRACTICAL GASTROENTEROLOGY • FEBRUARY 2008
               Nutritional Management of the Infant with Necrotizing Enterocolitis
               NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #59
              (continued from page 46)
              a recent study by Ostilie, et al (3), full term infants with       Table 1
              NEC were found to differ from preterm infants in sev-              Risk Factors for Necrotizing Enterocolitis (1,4,7–9)
              eral distinct ways. Full term infants developed NEC at
              a significantly earlier age (five days versus 13 days),            Risk Factor Category        Risk Factor Examples
              which may be attributed to having enteral feedings ini-            Maternal                    Prenatal indomethacin 
              tiated earlier. Furthermore, there was a clear association                                      therapy
              between congenital heart disease and the development                                           Placental insufficiency
              of NEC in the term infants. Interestingly, this study also                                     Cocaine use
              found no outcome differences between the term and
              preterm infants.                                                   Perinatal Prematurity
                                                                                                             Perinatal ischemia
              RISK FACTORS AND PATHOGENESIS                                                                  Hypoxic events
                                                                                 Postnatal Factors           Use of umbilical arterial 
              Risk Factors                                                                                    catheters
              Risk factors for NEC include maternal risk factors as                                          Ischemia of intestinal mucosa
              well as perinatal and postnatal risk factors related to                                        Congenital heart defects
              the infant’s clinical and infectious status in addition to                                     Rapid feeding advancements 
              their medical and nutritional management. The pre-                                             Use of hyperosmolar 
              dominant risk factors for NEC are presented in Table                                            formulas or medications
              1. Prematurity is one of the most significant risk fac-                                        Presence of infectious agents
              tors underlying NEC for a variety of reasons. Preterm
              infants have decreased immunocompetence, an imma-                 ments of formula volume. The impact of other factors,
              ture GI tract, and abnormal peristalsis. These factors            such as route, method of delivery, and the differences
              lead to nutrient maldigestion and malabsorption, set-             between breast milk, preterm formulas and term for-
              ting the stage for small intestinal bacterial overgrowth,         mulas on the incidence of NEC, however, are not as
              fermentation and ischemic damage to the premature                 clear (13). Studies looking at continuous versus bolus
              bowel. Decreased immunocompetence in preterm                      feedings in preterm infants have not demonstrated a
              infants increases the incidence of infections, including          difference in the incidence of NEC (1). Whether the
              pathogenic bacterial colonization of the GI tract.                use of human milk reduces the incidence of NEC
              Moreover, due to their increased incidence of car-                remains somewhat controversial due to limited data.
              diorespiratory, homeostatic instability and poor                  Most studies indicate that while breast milk reduces
              autoregulation of blood flow, preterm infants are more            the incidence of NEC, in some cases by one-half, it
              susceptible to ischemic or hypoxic events, putting                does not offer complete protection (12,13). 
              them at risk for NEC.
                  Feeding regimens, both formula composition as
              well as feeding approach, have been demonstrated to               Pathogenesis
              impact the development of neonatal NEC. Various                   The pathogenesis of NEC is thought to be related to
              studies conducted in the mid-to-late-seventies demon-             the interaction of a number of physiological mecha-
              strated a high incidence of NEC in infants fed hyper-             nisms including compromised mesenteric circulation,
              osmolar formulas and in those receiving medications               increased mucosal inflammation, and increased apop-
              and supplements added to the formula (10,11). More                tosis of the intestinal epithelial cells. Physiological
              than 90% of infants diagnosed with NEC have                       triggers leading to the inflammatory process are medi-
              received enteral nutrition (EN) (12). Enteral feeding             ated by factors including platelet-activating factor
              factors considered to increase the risk of NEC include            (PAF), thromboxanes, and cytokines, to name a few
              increased formula osmolality and rapid daily advance-             (13,14). Another reason for the increased risk of NEC
              48    PRACTICAL GASTROENTEROLOGY • FEBRUARY 2008
                                                  Nutritional Management of the Infant with Necrotizing Enterocolitis
                                                                  NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #58
               in preterm infants is their immature mucosal barrier,            Table 2
               which may potentiate the translocation of bacteria into          Bell’s Stages of Necrotizing Enterocolitis (16)
               the splanchnic bed and activate the inflammatory
               mediator cascade. Moreover, increased damage to the              Stage       Clinical Signs and Symptoms
               immature mucosal barrier may occur in preterms                   Stage 1     Broad spectrum but non-specific signs: 
               through the phenomenon of increased apoptosis, or                            simple feeding intolerance, sepsis, gastro-
               programmed cell death, thus further compromising the                         enteritis, ileus, metabolic abnormalities, 
               integrity of the mucosal barrier (14).                                       i.e. hypoglycemia
               CLINICAL PRESENTATION AND DIAGNOSIS                              Stage 2     Proven NEC via abdominal radiographs
                                                                                            showing intestinal dilatation and pneuma-
               The clinical presentation of NEC can vary significantly                      tosis intestinalis
               from one infant to another, ranging from mild to severe
               feeding intolerance or from mild abdominal distention to         Stage 3     Advanced stage in which infant demonstrates
               fulminant shock or death. Common clinical manifesta-                         signs of septic shock, metabolic acidosis,
               tions of NEC include increased gastric residual volumes,                     disseminated intravascular coagulopathy,
               increased emesis, increased abdominal distention, and                        neutropenia, abdominal tenderness, ascites
               mildly to grossly bloody stools (15). Gastric residual vol-
               umes indicative of feeding intolerance as a possible sign       practices such as strict handwashing, and the use of
               of early NEC is dependent on the infant’s weight and the        probiotic administration have also been found to have
               individual neonatal clinician. Laboratory abnormalities         a positive impact on the incidence of NEC (21,22). 
               include an elevated white blood cell count, neutropenia,            Minimal enteral nutrition or trophic feedings in the
               thrombocytopenia and disseminated intravascular coag-           first few weeks of life have been shown to decrease the
               ulation. In addition, the infant may experience metabolic       incidence of NEC in VLBW infants. Berseth, et al con-
               acidosis and electrolyte abnormalities. Pneumatosis             ducted a randomized controlled trial of 141 preterm
               intestinalis, or intraluminal gas produced by bacteria, is      infants, fed either a trophic schedule of 20 mL/kg/day
               considered to be the defining radiologic finding in the         for 10 days or an advancing schedule beginning at 20
               diagnosis of NEC; documented in 70%–80% of con-                 mL/kg on Day 1 and then advancing by 20 mL/kg/day
               firmed cases. Bell, et al established a staging system for      to a goal of 140 mL/kg (17). The incidence of NEC
               NEC, which has become a commonly used tool in its               was only 1.4% in the trophic group versus an inci-
               diagnosis and management. This staging system, pre-             dence of 10% in the advancing volumes group. A
               sented in Table 2, is based on clinical, radiographic and       recent meta-analysis conducted by Patole and de Klerk
               laboratory criteria (16).                                       (18) found that the use of standardized feeding regi-
                                                                               mens significantly reduced the incidence of NEC in
               PREVENTION STRATEGIES                                           preterm infants. Overall, the numerous studies con-
                                                                               ducted in this area have demonstrated that the variabil-
               Various prevention strategies have been identified              ity in GI response among preterm infants warrants
               which may decrease the incidence of NEC. These                  larger clinical trials to better characterize the mecha-
               include the use of trophic or minimal EN feedings,              nisms regulating feeding tolerance. 
               slow advancement of feedings, the use of standardized               Various recent studies have demonstrated that pro-
               feeding regimens, and the use of breast milk for EN             biotic administration has a positive impact on reducing
               (15,17,18). Additionally, the use of arginine supple-           the incidence of NEC (21,22). The widespread use of
               mentation as well as antenatal steroid, oral antibiotic         antibiotics in preterm infants in the NICU setting leads
               and immunoglobulin administration have been investi-            to a decrease in the colonization of the gut by commen-
               gated with regards to their potential role in the preven-       sural organisms such as Bifidobacterium and  Lacto-
               tion of NEC (19,20). Standardized infection control             bacillus species, and promotes the growth of pathogenic
                                                                               PRACTICAL GASTROENTEROLOGY • FEBRUARY 2008             49
                Nutritional Management of the Infant with Necrotizing Enterocolitis
                NUTRITION ISSUES IN GASTROENTEROLOGY, SERIES #59
                Table 3                                                                                   osmolality limitations and rarely pro-
                Estimated Calorie and Protein Needs for Infants (23,25,26)                                vides sufficient calories to prevent
                                                                                                          utilization of exogenous protein for
                                            Parenteral Enteral                                            fuel unless fluids are liberalized (23).
                Nutrient             Preterm         Term            Preterm         Term                     In medically-managed NEC,
                Calories/kg          85–115          85–100          110–130*        100–115*             duration of NPO status and full PN
                Protein gm/kg        3–4             2.4–2.8         3.5–4           2.8–3.5              support traditionally varies from
                                                                                                          seven days to two weeks, (24)
                *Catch up growth may require 10%–20% or more calories and higher levels of protein.       depending on severity of NEC, clini-
                                                                                                          cal indicators, and the results of
                                                                                                          abdominal evaluations. Surgery fur-
              organisms. The combination of pathogenic bacteria and                                       ther delays feedings. Given the
              an immature GI tract may be a clinical set-up for colo-                potential duration of PN, a key goal of nutritional man-
              nization of the bowel, the pathogenesis of NEC and,                    agement is provision of adequate, but not excessive,
              ultimately, bacterial translocation (21). Bin-Nun, et al               nutrients in order to prevent or delay the onset of PN-
              (22) found that the incidence of NEC in the infants ran-               related complications. 
              domized to receive daily supplementation with a probi-                      Estimated PN protein and calorie requirements for
              otic mixture was only 4% compared to the infants who                   preterm and term infants (23,25,26) are represented in
              did not receive the probiotic supplementation (16.4%),                 Table 3. Parenteral energy needs are estimated to be
              resulting in a relative risk reduction of 75%.                         10%–15% lower than EN needs due to reduced stool
                                                                                     losses and the absence of digestion and absorption
              NUTRITION FOLLOWING THE ONSET OF NEC                                   which are energy-requiring processes (23). The ELBW
              Despite preventive measures, the multiple risk factors                 infant may require closer to 105–115 kcal/kg (25–27).
              present in premature and critically ill term infants may               Whether NEC or sepsis increases energy needs signif-
              culminate in the diagnosis of NEC; the severity of                     icantly is unclear. Energy needs during the acute phase
              intestinal involvement influences the decision for                     of critical illness, with potential sedation and pain
              medical or surgical management. Each course of treat-                  medications given, may be close to basal needs, suffi-
              ment introduces particular nutritional concerns; how-                  cient to prevent catabolism and weight loss. Within
              ever, some aspects of nutritional management are                       one to three days postoperatively or post-acute
              common to both medical NEC and surgical NEC.                           response, energy needs likely return to normal or
                                                                                     greater, allowing for growth and movement (23,25).
                                                                                     Infants generally require at least 115 mL of fluid for
              PARENTERAL NUTRITION SUPPORT                                           every 100 kcal given (23,25). Nutrient and fluid deliv-
              Once NEC is strongly suspected and/or confirmed, the                   ery during and post-NEC require frequent monitoring.
              infant should be made NPO until deemed clinically                           Achieving growth during the acute phase of NEC
              ready for EN. Management of fluids and electrolytes is                 is difficult; this may be due to suboptimal delivery or
              critical in the initial phase of severe NEC, and intra-                reduced utilization of PN versus EN, or to the activa-
              venous fluids in addition to parenteral nutrition (PN)                 tion of cytokines and growth-impeding hormones in
              may be required to treat acidemia, support euvolemia,                  response to the inflammatory process. Adequate nutri-
              and adjust electrolytes. PN should be initiated as soon as             tion during the catabolic phase of NEC minimizes the
              possible, utilizing central access if adequate enteral sup-            loss of somatic proteins and provides for anabolism
              port will not be reached within two weeks (23). Ade-                   when the acute phase has passed. 
              quate protein and calories (kcal) are essential to prevent                  Micronutrient requirements may be affected by the
              breakdown of somatic protein for energy and for the                    inflammatory process. Zinc stores are diminished in
              production of inflammatory factors. Peripheral PN is                   the premature infant and most PN formulations pro-
              frequently restricted in nutrient concentration due to                                                        (continued on page 52)
               50     PRACTICAL GASTROENTEROLOGY • FEBRUARY 2008