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Preventing necrotizing enterocolitis in very low birth weight infants: current evidence
SYMPOSIUM: NEONATOLOGY
Preventing necrotizing enterocolitis in very low birth weight infants: current evidence
Clinical findings of NEC (modified Bell classification) I. ‘Suspected’ NEC: C Temperature instability, apnoea, bradycardia, lethargy C Gastric retention, abdominal distention, emesis, blood in stool C Normal, or intestinal dilation and mild ileus on abdominal radiograph II. ‘Definite’ NEC: C As above plus C Absent bowel sounds þ/ abdominal tenderness þ/ abdominal cellulitis or right lower quadrant mass C Radiological evidence of intestinal dilation, ileus, or pneumatosis intestinalis þ/ ascites III. ‘Advanced’ NEC: C As above plus C Hypotension, bradycardia, severe apnoea, respiratory and metabolic acidosis, coagulopathy, or neutropaenia C Signs of peritonitis, marked tenderness, and abdominal distention þ/ radiological evidence of intestinal perforation (pneumo-peritoneum)
Lauren Young Jessie Morgan William McGuire
Abstract Necrotizing enterocolitis (NEC) is the most common serious gastrointestinal disorder affecting very preterm or very low birth weight infants. The risk is inversely proportional to gestational age and weight at birth. Fetal growth restriction and compromise may be additional specific risk factors. Postnatally, a variety of practices have been implicated in the pathogenesis of NEC including formula milk feeding, early and rapid advancement of enteral feed volumes, and exposure to H2-receptor antagonists. NEC, particularly severe NEC requiring surgical intervention, is associated with acute morbidity and mortality, prolonged hospital stay, and adverse long-term neuro-developmental outcomes. With the exception of feeding with human milk, only limited evidence is currently available to support interventions to prevent NEC. Promising strategies that merit further evaluation in randomized controlled trials include the use of standardized feeding protocols and immuno-prophylaxis with prebiotics and probiotics.
Table 1
The rate of NEC-associated acute mortality is generally reported to be greater than 10% overall and more than 25% for infants with NEC severe enough to require a surgical intervention (which occurs in up to one-third of infants with NEC). VLBW infants who develop NEC experience more on-going morbidity than gestation-comparable infants who do not develop NEC. Infants with NEC have a higher incidence of nosocomial infections, lower levels of nutrient intake, grow more slowly, and have longer durations of intensive care and hospital stay. NEC, particularly severe NEC requiring surgical intervention, is also associated with a higher incidence of longterm neurological disability which may be a consequence of infection and under-nutrition during a critical period of brain development.
Keywords breast milk; lactoferrin; necrotizing enterocolitis; probiotics; very low birth weight
Epidemiology and outcomes
Pathogenesis and risk factors
Necrotizing enterocolitis (NEC) is a syndrome of acute intestinal necrosis of unknown aetiology affecting about 5% of all very preterm or very low birth weight (VLBW: <1500 g) and about 10% of all extremely preterm or extremely low birth weight (ELBW: <1000 g) infants (Table 1, Picture 1). Although treatment with antenatal corticosteroids reduces the risk of developing NEC by 50%, the overall incidence of NEC has not changed markedly in the past 20 years because of increases in early neonatal survival rates for extremely preterm and ELBW infants.
NEC is a postnatal condition e there are no reports of fetal NEC. The risk of developing NEC and the severity of the disease are
Lauren Young BSc MBBS is a Academic Clinical Fellow in Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none. Jessie Morgan MBBS is a Academic Clinical Fellow in Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none. William McGuire MD FRCPCH is Professor of Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none.
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Picture 1 Acute abdominal distention in NEC.
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SYMPOSIUM: NEONATOLOGY
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Enteral feeding Since most VLBW infants who develop NEC have received some milk feeds, it has long been postulated that differences between enteral feeding practices contribute to inter-unit variation in the incidence of NEC.
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genetic risk factors. Much larger family-based whole genome screening studies would be required to define important genetic contributions to NEC susceptibility. Because NEC is a sporadic disease which occurs infrequently in individual centres, this sort of investigation would require a co-ordinated multi-national effort to achieve recruitment of sufficient participants to provide a meaningful analysis.
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Breast milk versus formula milk Large observational studies undertaken in the late 1980’s demonstrated that infants who received their mother’s expressed breast milk as their primary source of enteral nutrition were 5e10 times less likely to develop NEC than infants fed with cow milk formula. However, because these studies did not randomly allocate infants to breast milk versus formula, the possibility that the effect on NEC was due to other known or unknown confounding factors cannot be excluded. For example, infants who did not receive maternal expressed milk may have had other risk factors for NEC such as intrauterine growth restriction. To date there have not been any randomized controlled trials of maternal breast milk versus formula milk feeding in VLBW infants. Such trials are now unlikely to be conducted because of lack of clinical and ethical equipoise. Several trials of feeding VLBW infants with donated expressed breast milk versus formula milk, either as the sole enteral diet or as a supplement when maternal breast milk is not available, have been conducted. Meta-analysis of these trials demonstrates a significantly higher risk of NEC in formula-fed infants (Figure 1). The decision to establish and maintain a service to provide donated breast milk for VLBW infants when maternal milk is not available requires further consideration of the feasibility, costs, and acceptability to parents. The key question is whether the substantial capital and opportunity costs of supplying donated breast milk would be better invested in promoting evidencebased practices to ensure mothers are optimally supported to express their own breast milk (see below).
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Picture 2 Preterm gestation and intrauterine growth restriction are risk factors for NEC.
inversely related to gestational age and weight at birth. The other putative major risk factor is intrauterine growth restriction secondary to suboptimal placental support (Picture 2). Although our understanding of the disease process remains incomplete, the currently accepted unifying model for the pathogenesis of NEC includes contribution and interaction of three key components: a susceptible immature gastrointestinal tract a precarious intestinal vascular supply (secondary to compensatory diversion to other vital organs) additional luminal factors secondary to milk feeding; increased intestinal metabolic demand, alteration of mucosal integrity, disturbance of optimal microbiological ecological balance, locally invasive gastrointestinal infection. Genetic contribution Studies comparing the concordance of disease in monozygotic versus dizygotic twins suggest that familial factors may contribute to the risk of NEC. However, association studies (usually small scale studies focussing on inflammatory mediators) have so far failed to detect any specific and substantial
Study or subgroup Goss 1983 Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983 Total (95% Cl)
Risk ratio M-H, Fixed, 95% Cl
Risk ratio M-H, Fixed, 95% Cl
4.73 [0.52, 43.09] 4.37 [0.50, 38.23] 2.46 [0.48, 12.49] 1.77 [0.63, 4.96] 2.53 [0.11, 60.39] 2.46 [1.19, 5.08]
Total events Heterogeneity: Chi2 = 0.99, df = 4 (P = 0.91); I2 = 0% Test for overall effect: Z = 2.43 (P = 0.02)
0.001
0.1
Favours formula milk
1
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Favours breast milk
Figure 1 Formula versus donor breast milk: meta-analysis of risk of NEC.
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SYMPOSIUM: NEONATOLOGY
Furthermore, because donated expressed breast milk generally contains fewer calories, protein and other nutrients that maternal milk, additional nutrient supplementation (typically with a commercially-available cow milk multi-nutrient fortifier) is usually used to promote growth and development. A recent North American multi-centre randomized controlled trial has demonstrated that use of a human milk multi-nutrient fortifier extracted from donated breast milk (rather than a cow milk fortifier) as an adjunct to feeding with maternal or donated expressed breast milk has an additional, synergistic effect in reducing risk of NEC in VLBW infants. Independent of individual decisions about use of donated breast milk, the above findings support the practice of encouraging all mothers to express breast milk for their VLBW infants. Several evidence-based interventions are available to support mothers to achieve this (Table 2, Picture 3). The challenge is to ensure that these are implemented consistently and broadly, and especially to vulnerable and socially-disadvantaged women who are less likely to provide expressed breast milk. Supporting mothers to express breast milk for their VLBW infants may be one of the most effective (and cost-effective) interventions currently available for reducing the incidence of NEC. Infant feeding practices in neonatal units, including the use of expressed breast milk, should be included in audit and benchmarking processes.
Picture 3 Electric pump to facilitate expression of maternal breast milk.
volumes. However, enteral fasting during the early neonatal period may have important disadvantages for VLBW infants. Because gastrointestinal hormone secretion and motility are stimulated by milk, delayed feeding could diminish the functional adaptation of the immature gastrointestinal tract with consequent intestinal dysmotility, feed intolerance, and further delay in establishing enteral feeding independently of parenteral nutrition. Prolonging the use of parenteral nutrition may be associated with infectious and metabolic complications that have adverse consequences for survival, duration of hospital stay, growth, and development. Although NEC is a devastating condition in the 5% of VLBW infants affected, preventative strategies, including conservative feeding regimens, need to be applied to all at risk infants. It has been argued that the ‘fear of NEC’ should not be considered in isolation of the other potential clinical outcomes in determining feeding policies and practice for VLBW infants (Figure 2).
Timing of introduction and rate of advancement of enteral feeds Audit and benchmarking studies have found that variation in the incidence of NEC between neonatal centres is not fully explained by case-mix and, after accounting for availability of breast milk, the incidence of NEC tends to be higher in neonatal units where enteral feeding is introduced earlier and feeding volumes are advanced quickly. Data from observational studies have also suggested that the timing of the introduction and the rate of advancement of the enteral feeding may be modifiable risk factors for the development of NEC in VLBW infants. However, the limited data currently available from randomized controlled trials are insufficient to determine which specific feeding strategies affect the risk of preterm infants developing NEC (Table 3).
Trophic feeding Trophic feeding (also known as minimal enteral nutrition, gut priming, hypo-caloric feeding) is an alternative to complete enteral fasting for VLBW infants during the early neonatal period. Trophic feeding is conventionally defined as giving small volumes of milk (up to 24 ml/kg/day) starting within the first few days after birth and continuing without increasing the volume of enteral feeds during the first postnatal week. The available data from randomized controlled trials do not indicate any major disadvantages; specifically there is no evidence that trophic feeding increases the risk of NEC (Figure 3). Importantly, evidence exists that mothers who express breast milk for early trophic feeding are more likely to continue to provide breast milk as the on-going principal form of nutrition for their infants. Only one randomized controlled trial has compared trophic feeding with progressive advancement of enteral feeds in VLBW infants. The investigators found the risk of NEC to be lower in infants who received prolonged trophic feeds. However, this finding needs to be interpreted and applied
Competing outcomes Given the paucity of high-level evidence, the currently recommended and implemented strategies for early enteral feeding of VLBW infants in the UK tend to be conservative and promote delayed introduction and slow progression of enteral feed
Interventions for lactation support for mothers of VLBW infants C C
C C
C
‘Kangaroo’ skin-to-skin contact between mother and infant Simultaneous expression of milk from both breasts (using electric pump) Peer support in hospital and community Multi-disciplinary staff training and continuous professional development to maintain skilled professional support UNICEF ‘Baby Friendly’ accreditation of the associated maternity hospital
Table 2
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Cochrane reviews of enteral feeding strategies and the risk of NEC Intervention Delayed introduction (>4 d) versus earlier feeding Slow advancement (<24 ml/kg/day) versus faster rates
Number of trials 4
Total participants 557
Typical relative risk for developing NEC (95% CI) 0.89 (0.58, 1.37)
4
496
0.91 (0.47e1.75)
Table 3
‘ADEPT’ Despite the potential for exacerbating nutritional disadvantage, enteral feeding for growth-restricted infants is often delayed for a week or more after birth. Paradoxically, this population of infants has usually been specifically excluded from participating in randomized controlled trials of early enteral feeding practices. The full results of the recently completed UK multi-centre trial (the ‘abnormal Doppler enteral prescription trail’ e ADEPT) examining the effect of delayed introduction of progressive enteral feeds on the risk of NEC and other morbidities in infants with severe growth restriction and evidence of circulatory redistribution are awaited (see: www.npeu.ox.ac.uk/adept/). The preliminary findings of ADEPT presented in abstract indicate that early feeds introduction results in earlier achievement of full enteral feeds. Unfortunately, even though with nearly 400 participants this is one of the largest trials of feeding strategies in VLBW infants, the study is insufficiently powered to exclude a plausible and important effect on the risk of NEC.
cautiously because it followed an interim analysis and may therefore be statistically spurious. In common with most feeding trials undertaken to date, caregivers and assessors were not blind to the intervention. This may have resulted in several sources of bias that are likely to cause an over-estimation of the incidence of NEC in infants whose feed volumes are being advanced. Furthermore, enteral feeds were not introduced until on average 10 days after birth, a practice that is not typical in most neonatal centres. Intra-uterine growth restriction Infants who are growth-restricted in utero are considered to have a higher risk of developing NEC, especially if there has been antenatal detection of ‘absent or reversed end-diastolic flow velocity’ (AREDFV) in Doppler studies of the fetal aorta or umbilical artery (Picture 4). Observational studies that have examined the association of AREDFV with NEC have reported inconsistent findings. This may be related to differences in study design, especially with regard to accounting for the confounding variables of gestational age and birth weight. However, more recent studies that matched case and control infants for gestational age and birth weight have generally not found significant associations of AREDFV with NEC. Further developments of Doppler velocimetry may allow more precise definition of compromised fetuses at risk of adverse neonatal outcomes, including NEC, by mapping flow in the mesenteric, hepatic and middle cerebral arteries. Early postnatal evaluation of superior mesenteric artery blood flow may also be developed as a tool to identify infants at increased risk of developing NEC.
Possible reduced risk of NEC
Standardized feeding protocols The use of standardized feeding protocols within neonatal centres is advocated as a means of ensuring uniformity of approach between clinicians in order to minimize confusion and frequent changes of practice. Additionally, despite the lack of robust evidence that specific methods of delivering enteral nutrition to VLBW infants affect important outcomes, a systematic review of observational studies has suggested that the use of a feeding protocol (irrespective of its specific recommendations) may of itself reduce the risk of NEC. However, the epochcomparison (‘before-after’) studies included in this review were unable to exclude other plausible reasons for the apparent decrease in the risk of NEC during the intervention (adoption of feeding protocol) phase. Better quality evidence from randomized or cluster-randomized trials is needed to assess this approach.
Delayed enteral and oral feeding Prolonged parenteral nutrition Gut atrophy Nosocomial infection Delayed hospital discharge
Immunoprotection One of the potential mechanisms by which feeding with human breast milk reduces the risk of NEC is the delivery of immunoprotective factors such as secretory immunoglobulin-A and lactoferrin to the immature small intestine. Another putative mechanism is that breast milk is ‘prebiotic’, that is, it contains substances that promote the growth of a non-pathogenic ‘probiotic’ intestinal microflora. These probiotic bacteria, predominantly Lactobacilli spp. and Bifidobacteria, in turn generate ‘postbiotic’ substances such as butyric acid that limits the growth of potential pathogens. It is feasible that enteral supplementation with these immuno-protective substances may reduce the risk of NEC in infants for whom human breast milk is not available.
Figure 2 Slow/delayed enteral feeding: balance of risks.
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Study or subgroup
Risk ratio M-H, Fixed, 95% Cl
Becerra 1996 Dunn 1988 Karagianni 2010 McClure 2000 Meetze 1992 Mosqueda 2008 Saenz de Pipaon Schanler 1999 Troche 1995 van Elburg 2004
1.31 [0.47, 3.62] 3.16 [0.36, 27.78] 1.54 [0.47, 5.04] 0.54 [0.05, 5.78] 0.79 [0.20, 3.09] 0.79 [0.19, 3.30] Not estimable 1.41 [0.65, 3.04] 0.16 [0.01, 3.16] 0.33 [0.01, 7.85]
Total (95% Cl)
1.12 [0.73, 1.73]
Risk ratio M-H, Fixed, 95% Cl
Total events Heterogeneity: Chi2 = 4.61, df = 8 (P = 0.80); I2 = 0% Test for overall effect: Z = 0.52 (P = 0.60)
0.002
0.1
1
Favours trophic feeding
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500
Favours fasting
Figure 3 Trophic feeding versus fasting: meta-analysis of risk of NEC.
Immunoglobulin Randomized controlled trials of enteric immunoglobulin supplementation for VLBW infants have not found any evidence of an effect on the incidence of NEC. However, most trials have used immunoglobulin-G whereas enteral immunoglobulin-A prophylaxis (which is more costly) is likely to be the more biologically appropriate intervention. Further trials are needed.
estimates of the included trials suggests that the size of the pooled estimate is due to publication bias. Finally, there remains concern that questions of safety, including the risk of invasive infection with probiotic bacteria, have not been addressed and the optimal strains and dose regimens have yet to be defined. On balance it seems appropriate and ethical at this stage to continue to support the large, good-quality, multi-centre trials of probiotic supplementation that are on-going internationally and to await a more precise and less biased estimate of effect size before introducing probiotic supplementation for VLBW infants as a routine practice.
Probiotics Some randomized controlled trials and meta-analyses of all of the available trials have found evidence that enteral administration of non-pathogenic probiotic species such as Lactobacilli and Bifidobacteria reduces the incidence of NEC, nosocomial infection, and mortality in VLBW infants. Some commentators have suggested that the current evidence-base is sufficient to adopt this intervention of a standard of care and that further controlled trials are unnecessary and unethical. Others advocate a more cautious and stepwise approach for several reasons. Firstly, although the pooled estimate from meta-analyses does indicate a substantially reduced risk of NEC and death, concern exists that these estimates are biased by various methodological weaknesses in the primary trials. Secondly, careful inspection of the distribution of effect size
Prebiotics Prebiotics, typically a mixture of galacto- and fructo-oligosaccharides, support the growth of probiotic Lactobacilli and Bifidobacteria in the bowel. Prebiotic substances are naturally present in breast milk and are resistant to gastric acid digestion. Feeding VLBW infants with formula milk supplemented with prebiotic substance stimulates the growth of an intestinal microflora that is similar to that found infants fed with human milk. To date, there have not been any large randomized controlled trials that have assessed the effect of prebiotics on the risk of NEC in VLBW infants but several such trails are being developed.
Picture 4 Doppler study of AREFV in fetal umbilical artery.
Lactoferrin supplementation Lactoferrin, an antimicrobial glycoprotein present in colostrum and breast milk, is a key component of the mammalian innate response to infection. Lactoferrin has broad microbicidal activity against Gram-positive cocci, Gram-negative bacilli, and Candida species. Lactoferrin also has prebiotic properties, creating an enteric environment for the growth of beneficial bacteria and reducing colonization with pathogenic species. VLBW infants have low lactoferrin levels and this deficiency is exacerbated by delay in establishing enteral feeding. A recently-published Italian multi-centre trial examined whether enteral supplementation with exogenous (bovine) lactoferrin for up to 6 weeks, either alone or in combination with a probiotic Lactobacillus, reduced the risk of NEC and invasive nosocomial infection in VLBW infants. This good-quality trial found evidence that
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Gastric acidity suppression Innate gastrointestinal immunity provided by gastric acid may be important in preventing the cascade of infectious and inflammatory events leading to NEC. A small-randomized controlled trial found that moderate acidification of milk with hydrochloric acid reduced the incidence of NEC in VLBW infants. Conversely, evidence exists that that the use of histamine-receptor type 2 (H2)-blockers to suppress gastric acidity is associated with a higher risk of NEC (and nosocomial infection) in VLBW infants. Given lack of evidence that gastro-oesophageal reflux is a cause of apnoea in preterm infants, it is recommended that use of H2-blockers should be restricted until robust evidence that benefits outweigh harmful effects is obtained.
lactoferrin supplementation reduced the incidence of invasive nosocomial infection by two-thirds compared with controls. However, the incidence of NEC was decreased in the lactoferrin plus probiotic group only. It is plausible that a more modest independent effect of lactoferrin on the risk of NEC may still exist and further large trials are proposed to investigate this possibility. Enteral antibiotics Evidence from controlled trials indicates that prophylactic enteral antibiotics (aminoglycoside or vancomycin) reduce the incidence of NEC in VLBW infants. There has been reluctance to adopt this practice because of concerns that such widespread antibiotic use would drive the emergence of antibiotic-resistant bacteria. Immuno-nutrition: glutamine and arginine VLBW infants who develop NEC have lower plasma levels of the amino acids arginine and glutamine compared with gestationcomparable infants who do not develop NEC. Glutamine is a ‘conditionally essential’ amino acid and is the preferred respiratory fuel for rapidly proliferating cells such as enterocytes. In animal models of experimental enterocolitis, glutamine supplementation reduces mucosal damage and lowers the risk of invasive infection and death. Glutamine is abundant in human milk but present only in much lower levels in cow milk formula and absent in standard parenteral nutrition solutions. Despite this biological plausibility, a Cochrane review and metaanalysis of good-quality randomized controlled trials did not find any evidence that the routine use of glutamine supplementation affects important clinical outcomes including the risk of developing NEC for VLBW infants. Instead, current research efforts have moved to assessing the potential of glutamine supplementation as a rescue therapy for accelerating recovery in infants with established NEC. Arginine is involved in the generation of nitric oxide, a key mediator of intestinal vasomotor tone. It has been suggested that enteral arginine supplementation may enhance endothelial nitric oxide generation and thereby improve intestinal perfusion. The only trial to have examined this intervention found a reduced incidence of NEC in infants who received arginine. A large multicentre trial is needed to confirm this finding.
Red blood cell transfusion Although several case reports have described infants developing NEC during red blood cell transfusion, a large randomized controlled trial of high versus low thresholds for red blood cell transfusion in ELBW infants did not find an effect on the incidence of NEC. The currently available evidence is insufficient to conclude that adopting a policy of enteral fasting during blood transfusion causes more benefit than harm.
Conclusion The currently identified major modifiable risk factors for the development of NEC in VLBW infants relates to enteral feeding practices. Evidence exists that feeding preterm infants with human breast milk rather than formula milk can reduce the risk of NEC. Substantial clinical uncertainty remains about the effect of strategies such as delaying the introduction of enteral feeds or slowly advancing feed volumes on the risk of NEC as well as other ‘competing’ outcomes, principally nosocomial infection secondary to prolonged use of parenteral nutrition. Other promising strategies for minimizing NEC that merit further evaluation include the use of prebiotics and probiotics, the avoidance of H2-receptor blockers, and the use of arginine supplementation. Large multi-centre trials within collaborative networks will be needed to address these questions. A
Other modifiable risk factors
FURTHER READING Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010; 125: 921e30. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005; 90: F359e63. Flidel-Rimon O, Branski D, Shinwell ES. The fear of necrotizing enterocolitis versus achieving optimal growth in preterm infantsean opinion. Acta Paediatr 2006; 95: 1341e4. Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117: e137e42. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519e23. Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005; 90: F147e51.
Umbilical arterial catheterization Umbilical artery catheters lying within the aorta could potentially disrupt intestinal perfusion directly or via micro-thrombotic emboli. The available data do not suggest that enteral feeding while an umbilical arterial catheter is in place affects superior mesenteric blood flow, the risk of feed intolerance, or the incidence of NEC. Patent ductus arteriosus and non-steroidal antiinflammatory agents The presence of a patent ductus arteriosus has been inconsistently reported as a risk factor for development of NEC in VLBW infants. No evidence exists that withholding enteral feeds in infants with a patent ductus arteriosus affects clinical outcomes including the risk of NEC. Furthermore, meta-analyses of goodquality randomized controlled trials of non-steroidal antiinflammatory agents for patent ductus arteriosus closure have not detected any significant effects on the incidence of NEC.
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Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2007: 4. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 2007; 92: F193e8. Renfrew MJ, Craig D, Dyson L, et al. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis. Health Technol Assess 2009; 13. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010; 156: 562e7. Tubman TRJ, Thompson SW, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2007: 4.
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The risk of necrotizing enterocolitis is inversely related to gestational age and weight at birth. Only limited evidence exists to suggest that conservative feeding strategies reduce the risk of NEC, and these three may be associated with other adverse (competing) outcomes including nosocomial infection. Injudicious use of gastric acid suppressants may be a risk factor for NEC. Promising new interventions to prevent NEC include probiotics and prebiotics but these require further evaluation in randomized controlled trials before being adopted as routine practice.
Crown Copyright Ó 2010 Published by Elsevier Ltd. All rights reserved.
Preventing necrotizing enterocolitis in very low birth weight infants: current evidence
Clinical findings of NEC (modified Bell classification) I. ‘Suspected’ NEC: C Temperature instability, apnoea, bradycardia, lethargy C Gastric retention, abdominal distention, emesis, blood in stool C Normal, or intestinal dilation and mild ileus on abdominal radiograph II. ‘Definite’ NEC: C As above plus C Absent bowel sounds þ/ abdominal tenderness þ/ abdominal cellulitis or right lower quadrant mass C Radiological evidence of intestinal dilation, ileus, or pneumatosis intestinalis þ/ ascites III. ‘Advanced’ NEC: C As above plus C Hypotension, bradycardia, severe apnoea, respiratory and metabolic acidosis, coagulopathy, or neutropaenia C Signs of peritonitis, marked tenderness, and abdominal distention þ/ radiological evidence of intestinal perforation (pneumo-peritoneum)
Lauren Young Jessie Morgan William McGuire
Abstract Necrotizing enterocolitis (NEC) is the most common serious gastrointestinal disorder affecting very preterm or very low birth weight infants. The risk is inversely proportional to gestational age and weight at birth. Fetal growth restriction and compromise may be additional specific risk factors. Postnatally, a variety of practices have been implicated in the pathogenesis of NEC including formula milk feeding, early and rapid advancement of enteral feed volumes, and exposure to H2-receptor antagonists. NEC, particularly severe NEC requiring surgical intervention, is associated with acute morbidity and mortality, prolonged hospital stay, and adverse long-term neuro-developmental outcomes. With the exception of feeding with human milk, only limited evidence is currently available to support interventions to prevent NEC. Promising strategies that merit further evaluation in randomized controlled trials include the use of standardized feeding protocols and immuno-prophylaxis with prebiotics and probiotics.
Table 1
The rate of NEC-associated acute mortality is generally reported to be greater than 10% overall and more than 25% for infants with NEC severe enough to require a surgical intervention (which occurs in up to one-third of infants with NEC). VLBW infants who develop NEC experience more on-going morbidity than gestation-comparable infants who do not develop NEC. Infants with NEC have a higher incidence of nosocomial infections, lower levels of nutrient intake, grow more slowly, and have longer durations of intensive care and hospital stay. NEC, particularly severe NEC requiring surgical intervention, is also associated with a higher incidence of longterm neurological disability which may be a consequence of infection and under-nutrition during a critical period of brain development.
Keywords breast milk; lactoferrin; necrotizing enterocolitis; probiotics; very low birth weight
Epidemiology and outcomes
Pathogenesis and risk factors
Necrotizing enterocolitis (NEC) is a syndrome of acute intestinal necrosis of unknown aetiology affecting about 5% of all very preterm or very low birth weight (VLBW: <1500 g) and about 10% of all extremely preterm or extremely low birth weight (ELBW: <1000 g) infants (Table 1, Picture 1). Although treatment with antenatal corticosteroids reduces the risk of developing NEC by 50%, the overall incidence of NEC has not changed markedly in the past 20 years because of increases in early neonatal survival rates for extremely preterm and ELBW infants.
NEC is a postnatal condition e there are no reports of fetal NEC. The risk of developing NEC and the severity of the disease are
Lauren Young BSc MBBS is a Academic Clinical Fellow in Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none. Jessie Morgan MBBS is a Academic Clinical Fellow in Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none. William McGuire MD FRCPCH is Professor of Child Health at Hull York Medical School, University of York, UK. Conflicts of interest: none.
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Picture 1 Acute abdominal distention in NEC.
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SYMPOSIUM: NEONATOLOGY
90 50 10
Head
Head (cm)
42
88
40
84
38
80
36
76
34
72 90 50 10
32 30
Length
28
68 64 60
26
56
24
52
Weight (kg)
44
50
7
Weight
Enteral feeding Since most VLBW infants who develop NEC have received some milk feeds, it has long been postulated that differences between enteral feeding practices contribute to inter-unit variation in the incidence of NEC.
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genetic risk factors. Much larger family-based whole genome screening studies would be required to define important genetic contributions to NEC susceptibility. Because NEC is a sporadic disease which occurs infrequently in individual centres, this sort of investigation would require a co-ordinated multi-national effort to achieve recruitment of sufficient participants to provide a meaningful analysis.
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Length (cm)
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6
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5
32
Breast milk versus formula milk Large observational studies undertaken in the late 1980’s demonstrated that infants who received their mother’s expressed breast milk as their primary source of enteral nutrition were 5e10 times less likely to develop NEC than infants fed with cow milk formula. However, because these studies did not randomly allocate infants to breast milk versus formula, the possibility that the effect on NEC was due to other known or unknown confounding factors cannot be excluded. For example, infants who did not receive maternal expressed milk may have had other risk factors for NEC such as intrauterine growth restriction. To date there have not been any randomized controlled trials of maternal breast milk versus formula milk feeding in VLBW infants. Such trials are now unlikely to be conducted because of lack of clinical and ethical equipoise. Several trials of feeding VLBW infants with donated expressed breast milk versus formula milk, either as the sole enteral diet or as a supplement when maternal breast milk is not available, have been conducted. Meta-analysis of these trials demonstrates a significantly higher risk of NEC in formula-fed infants (Figure 1). The decision to establish and maintain a service to provide donated breast milk for VLBW infants when maternal milk is not available requires further consideration of the feasibility, costs, and acceptability to parents. The key question is whether the substantial capital and opportunity costs of supplying donated breast milk would be better invested in promoting evidencebased practices to ensure mothers are optimally supported to express their own breast milk (see below).
4 3
Light for dates
2
Preterm 28 30 32 34 36 38 40
10
20
30
Picture 2 Preterm gestation and intrauterine growth restriction are risk factors for NEC.
inversely related to gestational age and weight at birth. The other putative major risk factor is intrauterine growth restriction secondary to suboptimal placental support (Picture 2). Although our understanding of the disease process remains incomplete, the currently accepted unifying model for the pathogenesis of NEC includes contribution and interaction of three key components: a susceptible immature gastrointestinal tract a precarious intestinal vascular supply (secondary to compensatory diversion to other vital organs) additional luminal factors secondary to milk feeding; increased intestinal metabolic demand, alteration of mucosal integrity, disturbance of optimal microbiological ecological balance, locally invasive gastrointestinal infection. Genetic contribution Studies comparing the concordance of disease in monozygotic versus dizygotic twins suggest that familial factors may contribute to the risk of NEC. However, association studies (usually small scale studies focussing on inflammatory mediators) have so far failed to detect any specific and substantial
Study or subgroup Goss 1983 Lucas 1984a Lucas 1984b Schanler 2005 Tyson 1983 Total (95% Cl)
Risk ratio M-H, Fixed, 95% Cl
Risk ratio M-H, Fixed, 95% Cl
4.73 [0.52, 43.09] 4.37 [0.50, 38.23] 2.46 [0.48, 12.49] 1.77 [0.63, 4.96] 2.53 [0.11, 60.39] 2.46 [1.19, 5.08]
Total events Heterogeneity: Chi2 = 0.99, df = 4 (P = 0.91); I2 = 0% Test for overall effect: Z = 2.43 (P = 0.02)
0.001
0.1
Favours formula milk
1
10
1000
Favours breast milk
Figure 1 Formula versus donor breast milk: meta-analysis of risk of NEC.
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Furthermore, because donated expressed breast milk generally contains fewer calories, protein and other nutrients that maternal milk, additional nutrient supplementation (typically with a commercially-available cow milk multi-nutrient fortifier) is usually used to promote growth and development. A recent North American multi-centre randomized controlled trial has demonstrated that use of a human milk multi-nutrient fortifier extracted from donated breast milk (rather than a cow milk fortifier) as an adjunct to feeding with maternal or donated expressed breast milk has an additional, synergistic effect in reducing risk of NEC in VLBW infants. Independent of individual decisions about use of donated breast milk, the above findings support the practice of encouraging all mothers to express breast milk for their VLBW infants. Several evidence-based interventions are available to support mothers to achieve this (Table 2, Picture 3). The challenge is to ensure that these are implemented consistently and broadly, and especially to vulnerable and socially-disadvantaged women who are less likely to provide expressed breast milk. Supporting mothers to express breast milk for their VLBW infants may be one of the most effective (and cost-effective) interventions currently available for reducing the incidence of NEC. Infant feeding practices in neonatal units, including the use of expressed breast milk, should be included in audit and benchmarking processes.
Picture 3 Electric pump to facilitate expression of maternal breast milk.
volumes. However, enteral fasting during the early neonatal period may have important disadvantages for VLBW infants. Because gastrointestinal hormone secretion and motility are stimulated by milk, delayed feeding could diminish the functional adaptation of the immature gastrointestinal tract with consequent intestinal dysmotility, feed intolerance, and further delay in establishing enteral feeding independently of parenteral nutrition. Prolonging the use of parenteral nutrition may be associated with infectious and metabolic complications that have adverse consequences for survival, duration of hospital stay, growth, and development. Although NEC is a devastating condition in the 5% of VLBW infants affected, preventative strategies, including conservative feeding regimens, need to be applied to all at risk infants. It has been argued that the ‘fear of NEC’ should not be considered in isolation of the other potential clinical outcomes in determining feeding policies and practice for VLBW infants (Figure 2).
Timing of introduction and rate of advancement of enteral feeds Audit and benchmarking studies have found that variation in the incidence of NEC between neonatal centres is not fully explained by case-mix and, after accounting for availability of breast milk, the incidence of NEC tends to be higher in neonatal units where enteral feeding is introduced earlier and feeding volumes are advanced quickly. Data from observational studies have also suggested that the timing of the introduction and the rate of advancement of the enteral feeding may be modifiable risk factors for the development of NEC in VLBW infants. However, the limited data currently available from randomized controlled trials are insufficient to determine which specific feeding strategies affect the risk of preterm infants developing NEC (Table 3).
Trophic feeding Trophic feeding (also known as minimal enteral nutrition, gut priming, hypo-caloric feeding) is an alternative to complete enteral fasting for VLBW infants during the early neonatal period. Trophic feeding is conventionally defined as giving small volumes of milk (up to 24 ml/kg/day) starting within the first few days after birth and continuing without increasing the volume of enteral feeds during the first postnatal week. The available data from randomized controlled trials do not indicate any major disadvantages; specifically there is no evidence that trophic feeding increases the risk of NEC (Figure 3). Importantly, evidence exists that mothers who express breast milk for early trophic feeding are more likely to continue to provide breast milk as the on-going principal form of nutrition for their infants. Only one randomized controlled trial has compared trophic feeding with progressive advancement of enteral feeds in VLBW infants. The investigators found the risk of NEC to be lower in infants who received prolonged trophic feeds. However, this finding needs to be interpreted and applied
Competing outcomes Given the paucity of high-level evidence, the currently recommended and implemented strategies for early enteral feeding of VLBW infants in the UK tend to be conservative and promote delayed introduction and slow progression of enteral feed
Interventions for lactation support for mothers of VLBW infants C C
C C
C
‘Kangaroo’ skin-to-skin contact between mother and infant Simultaneous expression of milk from both breasts (using electric pump) Peer support in hospital and community Multi-disciplinary staff training and continuous professional development to maintain skilled professional support UNICEF ‘Baby Friendly’ accreditation of the associated maternity hospital
Table 2
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Cochrane reviews of enteral feeding strategies and the risk of NEC Intervention Delayed introduction (>4 d) versus earlier feeding Slow advancement (<24 ml/kg/day) versus faster rates
Number of trials 4
Total participants 557
Typical relative risk for developing NEC (95% CI) 0.89 (0.58, 1.37)
4
496
0.91 (0.47e1.75)
Table 3
‘ADEPT’ Despite the potential for exacerbating nutritional disadvantage, enteral feeding for growth-restricted infants is often delayed for a week or more after birth. Paradoxically, this population of infants has usually been specifically excluded from participating in randomized controlled trials of early enteral feeding practices. The full results of the recently completed UK multi-centre trial (the ‘abnormal Doppler enteral prescription trail’ e ADEPT) examining the effect of delayed introduction of progressive enteral feeds on the risk of NEC and other morbidities in infants with severe growth restriction and evidence of circulatory redistribution are awaited (see: www.npeu.ox.ac.uk/adept/). The preliminary findings of ADEPT presented in abstract indicate that early feeds introduction results in earlier achievement of full enteral feeds. Unfortunately, even though with nearly 400 participants this is one of the largest trials of feeding strategies in VLBW infants, the study is insufficiently powered to exclude a plausible and important effect on the risk of NEC.
cautiously because it followed an interim analysis and may therefore be statistically spurious. In common with most feeding trials undertaken to date, caregivers and assessors were not blind to the intervention. This may have resulted in several sources of bias that are likely to cause an over-estimation of the incidence of NEC in infants whose feed volumes are being advanced. Furthermore, enteral feeds were not introduced until on average 10 days after birth, a practice that is not typical in most neonatal centres. Intra-uterine growth restriction Infants who are growth-restricted in utero are considered to have a higher risk of developing NEC, especially if there has been antenatal detection of ‘absent or reversed end-diastolic flow velocity’ (AREDFV) in Doppler studies of the fetal aorta or umbilical artery (Picture 4). Observational studies that have examined the association of AREDFV with NEC have reported inconsistent findings. This may be related to differences in study design, especially with regard to accounting for the confounding variables of gestational age and birth weight. However, more recent studies that matched case and control infants for gestational age and birth weight have generally not found significant associations of AREDFV with NEC. Further developments of Doppler velocimetry may allow more precise definition of compromised fetuses at risk of adverse neonatal outcomes, including NEC, by mapping flow in the mesenteric, hepatic and middle cerebral arteries. Early postnatal evaluation of superior mesenteric artery blood flow may also be developed as a tool to identify infants at increased risk of developing NEC.
Possible reduced risk of NEC
Standardized feeding protocols The use of standardized feeding protocols within neonatal centres is advocated as a means of ensuring uniformity of approach between clinicians in order to minimize confusion and frequent changes of practice. Additionally, despite the lack of robust evidence that specific methods of delivering enteral nutrition to VLBW infants affect important outcomes, a systematic review of observational studies has suggested that the use of a feeding protocol (irrespective of its specific recommendations) may of itself reduce the risk of NEC. However, the epochcomparison (‘before-after’) studies included in this review were unable to exclude other plausible reasons for the apparent decrease in the risk of NEC during the intervention (adoption of feeding protocol) phase. Better quality evidence from randomized or cluster-randomized trials is needed to assess this approach.
Delayed enteral and oral feeding Prolonged parenteral nutrition Gut atrophy Nosocomial infection Delayed hospital discharge
Immunoprotection One of the potential mechanisms by which feeding with human breast milk reduces the risk of NEC is the delivery of immunoprotective factors such as secretory immunoglobulin-A and lactoferrin to the immature small intestine. Another putative mechanism is that breast milk is ‘prebiotic’, that is, it contains substances that promote the growth of a non-pathogenic ‘probiotic’ intestinal microflora. These probiotic bacteria, predominantly Lactobacilli spp. and Bifidobacteria, in turn generate ‘postbiotic’ substances such as butyric acid that limits the growth of potential pathogens. It is feasible that enteral supplementation with these immuno-protective substances may reduce the risk of NEC in infants for whom human breast milk is not available.
Figure 2 Slow/delayed enteral feeding: balance of risks.
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Study or subgroup
Risk ratio M-H, Fixed, 95% Cl
Becerra 1996 Dunn 1988 Karagianni 2010 McClure 2000 Meetze 1992 Mosqueda 2008 Saenz de Pipaon Schanler 1999 Troche 1995 van Elburg 2004
1.31 [0.47, 3.62] 3.16 [0.36, 27.78] 1.54 [0.47, 5.04] 0.54 [0.05, 5.78] 0.79 [0.20, 3.09] 0.79 [0.19, 3.30] Not estimable 1.41 [0.65, 3.04] 0.16 [0.01, 3.16] 0.33 [0.01, 7.85]
Total (95% Cl)
1.12 [0.73, 1.73]
Risk ratio M-H, Fixed, 95% Cl
Total events Heterogeneity: Chi2 = 4.61, df = 8 (P = 0.80); I2 = 0% Test for overall effect: Z = 0.52 (P = 0.60)
0.002
0.1
1
Favours trophic feeding
10
500
Favours fasting
Figure 3 Trophic feeding versus fasting: meta-analysis of risk of NEC.
Immunoglobulin Randomized controlled trials of enteric immunoglobulin supplementation for VLBW infants have not found any evidence of an effect on the incidence of NEC. However, most trials have used immunoglobulin-G whereas enteral immunoglobulin-A prophylaxis (which is more costly) is likely to be the more biologically appropriate intervention. Further trials are needed.
estimates of the included trials suggests that the size of the pooled estimate is due to publication bias. Finally, there remains concern that questions of safety, including the risk of invasive infection with probiotic bacteria, have not been addressed and the optimal strains and dose regimens have yet to be defined. On balance it seems appropriate and ethical at this stage to continue to support the large, good-quality, multi-centre trials of probiotic supplementation that are on-going internationally and to await a more precise and less biased estimate of effect size before introducing probiotic supplementation for VLBW infants as a routine practice.
Probiotics Some randomized controlled trials and meta-analyses of all of the available trials have found evidence that enteral administration of non-pathogenic probiotic species such as Lactobacilli and Bifidobacteria reduces the incidence of NEC, nosocomial infection, and mortality in VLBW infants. Some commentators have suggested that the current evidence-base is sufficient to adopt this intervention of a standard of care and that further controlled trials are unnecessary and unethical. Others advocate a more cautious and stepwise approach for several reasons. Firstly, although the pooled estimate from meta-analyses does indicate a substantially reduced risk of NEC and death, concern exists that these estimates are biased by various methodological weaknesses in the primary trials. Secondly, careful inspection of the distribution of effect size
Prebiotics Prebiotics, typically a mixture of galacto- and fructo-oligosaccharides, support the growth of probiotic Lactobacilli and Bifidobacteria in the bowel. Prebiotic substances are naturally present in breast milk and are resistant to gastric acid digestion. Feeding VLBW infants with formula milk supplemented with prebiotic substance stimulates the growth of an intestinal microflora that is similar to that found infants fed with human milk. To date, there have not been any large randomized controlled trials that have assessed the effect of prebiotics on the risk of NEC in VLBW infants but several such trails are being developed.
Picture 4 Doppler study of AREFV in fetal umbilical artery.
Lactoferrin supplementation Lactoferrin, an antimicrobial glycoprotein present in colostrum and breast milk, is a key component of the mammalian innate response to infection. Lactoferrin has broad microbicidal activity against Gram-positive cocci, Gram-negative bacilli, and Candida species. Lactoferrin also has prebiotic properties, creating an enteric environment for the growth of beneficial bacteria and reducing colonization with pathogenic species. VLBW infants have low lactoferrin levels and this deficiency is exacerbated by delay in establishing enteral feeding. A recently-published Italian multi-centre trial examined whether enteral supplementation with exogenous (bovine) lactoferrin for up to 6 weeks, either alone or in combination with a probiotic Lactobacillus, reduced the risk of NEC and invasive nosocomial infection in VLBW infants. This good-quality trial found evidence that
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Gastric acidity suppression Innate gastrointestinal immunity provided by gastric acid may be important in preventing the cascade of infectious and inflammatory events leading to NEC. A small-randomized controlled trial found that moderate acidification of milk with hydrochloric acid reduced the incidence of NEC in VLBW infants. Conversely, evidence exists that that the use of histamine-receptor type 2 (H2)-blockers to suppress gastric acidity is associated with a higher risk of NEC (and nosocomial infection) in VLBW infants. Given lack of evidence that gastro-oesophageal reflux is a cause of apnoea in preterm infants, it is recommended that use of H2-blockers should be restricted until robust evidence that benefits outweigh harmful effects is obtained.
lactoferrin supplementation reduced the incidence of invasive nosocomial infection by two-thirds compared with controls. However, the incidence of NEC was decreased in the lactoferrin plus probiotic group only. It is plausible that a more modest independent effect of lactoferrin on the risk of NEC may still exist and further large trials are proposed to investigate this possibility. Enteral antibiotics Evidence from controlled trials indicates that prophylactic enteral antibiotics (aminoglycoside or vancomycin) reduce the incidence of NEC in VLBW infants. There has been reluctance to adopt this practice because of concerns that such widespread antibiotic use would drive the emergence of antibiotic-resistant bacteria. Immuno-nutrition: glutamine and arginine VLBW infants who develop NEC have lower plasma levels of the amino acids arginine and glutamine compared with gestationcomparable infants who do not develop NEC. Glutamine is a ‘conditionally essential’ amino acid and is the preferred respiratory fuel for rapidly proliferating cells such as enterocytes. In animal models of experimental enterocolitis, glutamine supplementation reduces mucosal damage and lowers the risk of invasive infection and death. Glutamine is abundant in human milk but present only in much lower levels in cow milk formula and absent in standard parenteral nutrition solutions. Despite this biological plausibility, a Cochrane review and metaanalysis of good-quality randomized controlled trials did not find any evidence that the routine use of glutamine supplementation affects important clinical outcomes including the risk of developing NEC for VLBW infants. Instead, current research efforts have moved to assessing the potential of glutamine supplementation as a rescue therapy for accelerating recovery in infants with established NEC. Arginine is involved in the generation of nitric oxide, a key mediator of intestinal vasomotor tone. It has been suggested that enteral arginine supplementation may enhance endothelial nitric oxide generation and thereby improve intestinal perfusion. The only trial to have examined this intervention found a reduced incidence of NEC in infants who received arginine. A large multicentre trial is needed to confirm this finding.
Red blood cell transfusion Although several case reports have described infants developing NEC during red blood cell transfusion, a large randomized controlled trial of high versus low thresholds for red blood cell transfusion in ELBW infants did not find an effect on the incidence of NEC. The currently available evidence is insufficient to conclude that adopting a policy of enteral fasting during blood transfusion causes more benefit than harm.
Conclusion The currently identified major modifiable risk factors for the development of NEC in VLBW infants relates to enteral feeding practices. Evidence exists that feeding preterm infants with human breast milk rather than formula milk can reduce the risk of NEC. Substantial clinical uncertainty remains about the effect of strategies such as delaying the introduction of enteral feeds or slowly advancing feed volumes on the risk of NEC as well as other ‘competing’ outcomes, principally nosocomial infection secondary to prolonged use of parenteral nutrition. Other promising strategies for minimizing NEC that merit further evaluation include the use of prebiotics and probiotics, the avoidance of H2-receptor blockers, and the use of arginine supplementation. Large multi-centre trials within collaborative networks will be needed to address these questions. A
Other modifiable risk factors
FURTHER READING Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010; 125: 921e30. Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Arch Dis Child Fetal Neonatal Ed 2005; 90: F359e63. Flidel-Rimon O, Branski D, Shinwell ES. The fear of necrotizing enterocolitis versus achieving optimal growth in preterm infantsean opinion. Acta Paediatr 2006; 95: 1341e4. Guillet R, Stoll BJ, Cotten CM, et al. Association of H2-blocker therapy and higher incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2006; 117: e137e42. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet 1990; 336: 1519e23. Patole SK, de Klerk N. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child Fetal Neonatal Ed 2005; 90: F147e51.
Umbilical arterial catheterization Umbilical artery catheters lying within the aorta could potentially disrupt intestinal perfusion directly or via micro-thrombotic emboli. The available data do not suggest that enteral feeding while an umbilical arterial catheter is in place affects superior mesenteric blood flow, the risk of feed intolerance, or the incidence of NEC. Patent ductus arteriosus and non-steroidal antiinflammatory agents The presence of a patent ductus arteriosus has been inconsistently reported as a risk factor for development of NEC in VLBW infants. No evidence exists that withholding enteral feeds in infants with a patent ductus arteriosus affects clinical outcomes including the risk of NEC. Furthermore, meta-analyses of goodquality randomized controlled trials of non-steroidal antiinflammatory agents for patent ductus arteriosus closure have not detected any significant effects on the incidence of NEC.
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Quigley MA, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev 2007: 4. Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Arch Dis Child Fetal Neonatal Ed 2007; 92: F193e8. Renfrew MJ, Craig D, Dyson L, et al. Breastfeeding promotion for infants in neonatal units: a systematic review and economic analysis. Health Technol Assess 2009; 13. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 2010; 156: 562e7. Tubman TRJ, Thompson SW, McGuire W. Glutamine supplementation to prevent morbidity and mortality in preterm infants. Cochrane Database Syst Rev 2007: 4.
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C
C
C
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The risk of necrotizing enterocolitis is inversely related to gestational age and weight at birth. Only limited evidence exists to suggest that conservative feeding strategies reduce the risk of NEC, and these three may be associated with other adverse (competing) outcomes including nosocomial infection. Injudicious use of gastric acid suppressants may be a risk factor for NEC. Promising new interventions to prevent NEC include probiotics and prebiotics but these require further evaluation in randomized controlled trials before being adopted as routine practice.
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