Description of the condition
Necrotising enterocolitis is an important cause of morbidity, mortality and neuro-disability in very low birth weight infants. Extremely low birth weight and extremely preterm infants are at greatest risk (Bisquera 2002; Holman 2006; Rees 2007). Intrauterine growth restriction may be an additional specific risk factor, especially if associated with circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in antenatal Doppler studies of the fetal aorta or umbilical artery (Bernstein 2000; Garite 2004; Dorling 2005; Kamoji 2008).
Description of the intervention
Most very low birth weight infants who develop necrotising enterocolitis have received enteral milk feeds. Evidence exists that feeding with formula milk increases the risk (Lucas 1990; Quigley 2007). The timing of the introduction and the rate of progression of enteral feed volumes may also be modifiable risk factors for the development of necrotising enterocolitis (Brown 1978; Uauy 1991; Henderson 2009). Data from observational studies suggest that using feeding regimens that include delaying the introduction of progressive enteral feeds for about five to seven days after birth reduces the risk of necrotising enterocolitis (Patole 2005; Hay 2008).
Why it is important to do this review
In current clinical practice, the introduction of progressive enteral feeds for very low birth weight infants is often preceded by a period of enteral fasting or "trophic feeding" (feeding small volumes up to 24 ml/kg/day) (Boyle 2004; Patole 2004; Hay 2008). However, there may also be potential disadvantages associated with delaying the introduction of progressive enteral feeds. Because gastrointestinal hormone secretion and motility are stimulated by enteral milk, delayed enteral feeding could diminish the functional adaptation of the gastrointestinal tract (Berseth 1990; Burrin 2002). Prolonging the duration of use of parenteral nutrition may be associated with infectious and metabolic complications that increase mortality and morbidity, prolong hospital stay, and adversely affect growth and development (Flidel-Rimon 2004; Stoll 2004). It has been argued that the risk of necrotising enterocolitis should not be considered in isolation of these other potential clinical outcomes when determining feeding policies and practice for very low birth weight infants (Flidel-Rimon 2006; Hay 2008; Hartel 2009).
This review focuses on the comparison of delayed versus earlier introduction of progressive enteral feeding; that is, advancing the volume of milk feeds beyond "trophic" levels. The effect of trophic feeding, the early introduction of small volume enteral feeds (up to 24 ml/kg/day) without advancing the feed volumes for at least five days versus enteral fasting is addressed in the Cochrane review "Early trophic feeding for very low birth weight infants" (Bombell 2009).
To determine the effect of delayed the introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very low birth weight infants.
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials or cluster randomised trials.
Types of participants
Very low birth weight (<1500 grams) or very preterm (<32 weeks' gestation) newborn infants.
Types of interventions
Delayed introduction (more than four days after birth) of progressive enteral feeds versus earlier introduction of enteral feeds. Progressive enteral feeding is defined as the intention to advance feed volumes in excess of trophic feeds (up to 24 ml/kg/day) within five days of commencement or by one week after birth.
Infants in each group should have received the same type of milk (breast milk or formula), the same route and mode of feeding (intragastric or transpyloric, bolus gavage or continuous) and the same rate of feed volume advancement in both groups.
Types of outcome measures
1. Necrotising enterocolitis confirmed by at least two of the following features:
- abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen
- abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both)
- blood in stool
- lethargy, hypotonia, or apnoea (or combination of these);
or a diagnosis confirmed at surgery or autopsy (Walsh 1986).
2. All-cause mortality during the neonatal period and prior to hospital discharge.
3. Growth: (i) Time to regain birth weight and subsequent rates of weight gain, linear growth, head growth, or skinfold thickness growth up to six months' (corrected for preterm birth).
(ii) Long-term growth: weight, height, or head circumference (and/or proportion of infants who remain below the tenth percentile for the index population's distribution) assessed at intervals from six months of age.
4. Neurodevelopment: (i) Death or severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component will be analysed individually as well as part of the composite outcome.
(ii) Neurodevelopmental scores in survivors aged greater than, or equal to, 12 months' of age measured using validated assessment tools.
(iii) Cognitive and educational outcomes in survivors aged more than five years old.
5. Time to establish full enteral feeding (independently of parenteral nutrition).
6. Time to establish oral feeding (independently of parenteral nutrition and/or enteral tube feeding).
7. Feed intolerance (defined as a requirement to cease enteral feeds).
8. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine, or from a normally sterile body space.
9. Duration of hospital stay (days).
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal Review Group.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2010, Issue 4), MEDLINE (1966 to December 2010), EMBASE (1980 to December 2010), and CINAHL (1982 to December 2010) using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR Infant, Very Low Birth Weight/ OR infan* OR neonat* OR preterm OR prem*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula OR trophic feeding OR minimal enteral nutrition OR gut priming]. The search outputs were limited with the relevant search filters for clinical trials as recommended in the Cochrane Handbook. A language restriction was not applied.
Searching other resources
We examined the references in all studies identified as potentially relevant.
We searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 - 2010), the European Society for Pediatric Research (1995 - 2010), the UK Royal College of Paediatrics and Child Health (2000 - 2010), and the Perinatal Society of Australia and New Zealand (2000 to 2010). Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review Group.
Selection of studies
Two reviewers screened the title and abstract of all studies identified by the above search strategy. The full text of any potentially eligible reports was reassessed and those studies that did not meet all of the inclusion criteria were excluded. We discussed any disagreements until consensus was achieved.
Data extraction and management
We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the investigators were contacted for further information.
Assessment of risk of bias in included studies
The criteria and standard methods of the Cochrane Neonatal Review Group were used to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. The following issues were evaluated and reported in the Risk of Bias tables:
(1) Sequence generation: Was the allocation sequence adequately generated? We categorised the method used to generate the allocation sequence as:
- adequate (any random process e.g. random number table; computer random number generator);
- inadequate (any non random process e.g. odd or even date of birth; patient case-record number);
(2) Allocation concealment: Was allocation adequately concealed? We categorised the method used to conceal the allocation sequence as:
- adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
- inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
(3) Blinding: Was knowledge of the allocated intervention adequately prevented at study entry, during the study, and at the time of outcome assessment? We assessed blinding separately for different outcomes and categorised the methods as adequate, inadequate or unclear for participants, clinicians and caregivers, and outcome assessors.
(4) Incomplete outcome data: Were incomplete outcome data adequately addressed? We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:
- adequate (< 20% missing data);
- inadequate (≥ 20% missing data);
(5) Selective reporting bias. Were reports of the study free of suggestion of selective outcome reporting? We aimed to assess whether methods were:
- adequate (clear that all of the trial’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
- inadequate (where not all the trial’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
Measures of treatment effect
We calculated relative risk (RR) and risk difference (RD) for dichotomous data and weighted mean difference (WMD) for continuous data, with respective 95% confidence intervals (CI). The number needed to treat for benefit (NNTB) or harm (NNTH) was determined for a statistically significant difference in the RD.
Unit of analysis issues
The unit on analysis is the participating infant in individually randomised trials and the neonatal unit (or sub-unit) for cluster randomised trials.
Assessment of heterogeneity
If more than one trial was included in a meta-analysis, we examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses.
We used the fixed effects model in RevMan 5 for meta-analysis.
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
- Trials in which most infants were exclusively formula milk-fed.
- Trials in which most infants were at least partially fed with breast milk (maternal or donor).
- Trials in which most participants were of extremely low birth weight (less than 1000 grams) or extremely preterm gestational age (less than 28 weeks').
- Trials in which participants were infants with intrauterine growth restriction, or infants with absent or reversed end-diastolic flow velocities detected on antenatal Doppler studies of the fetal aorta or umbilical artery.
Description of studies
A total of 600 infants participated in the included trials.
The three older trials were undertaken in neonatal care centres in North America during the 1980s and early 1990s:
- Ostertag 1986; Very low birth weight infants (N= 38). Infants were eligible to participate if they were assessed with a risk score to be at high risk of developing necrotising enterocolitis.
- Khayata 1987; Very low birth weight infants (N= 12).
- Davey 1994; Clinically stable preterm infants of birth weight <2000 grams who had a low umbilical artery catheter in situ (N = 62). Since most participants were of birth weight <1500 grams or gestational age <32 weeks', a consensus decision to include the trial was made.
The two more recent trials were performed within the past 5 years. One trial (N= 84) was undertaken in a single centre in Greece (Karagianni 2010). A larger trial (N= 404) was undertaken across 54 centres in the UK and Ireland (Leaf 2010). In both, the eligibility criteria were (i) <35 weeks' gestation, (ii) birth weight <10th percentile, and (iii) evidence of abnormal fetal blood flow patterns on Doppler ultrasound studies (see Characteristics of included studies).
- "Earlier" feeding varied from day 1 to day 4 after birth.
In three trials infants received either breast milk or diluted formula (Davey 1994; Karagianni 2010; Leaf 2010). In two trials only formula milk fed infants participated (Ostertag 1986; Khayata 1987). Infants received enteral feeds by gavage at one hourly intervals in all of the trials except Ostertag 1986 where infants received feeds by continuous intragastric infusion.
All of the trial protocols, except that of the smallest trial (Khayata 1987), specified criteria and indications for advancing (daily increments of 15- 20 ml/kg) or interrupting enteral feed (for example, residual gastric contents not >3- 5 ml or one-third to one-half of the previous feed volume, frequent vomiting, abdominal distention, or detection of blood in the stools).
All of the trials reported the incidence of necrotising enterocolitis (Bell stage II/III: confirmed radiologically, or at surgery or autopsy). The other reported outcomes included time to establish full enteral feeding and duration of hospital stay. Only one trial reported the incidence of invasive infection (Leaf 2010).
Risk of bias in included studies
Quality assessments are included in the Table, 'Characteristics of included studies'.
The smallest trial (N= 12) was reported in abstract form only and methodological details were not described (Khayata 1987). The other trials all appear to be of generally good quality. In all four trials methods to ensure adequate allocation concealment were employed. None of the trials was able to conceal the feeding strategies from parents, caregivers or clinical investigators but the assessment of abdominal radiographs (for diagnosis of necrotising enterocolitis) was masked. Complete or near-complete assessments of the primary outcomes were reported and data were available to undertake intention-to-treat analyses as required.
Effects of interventions
DELAYED VS. EARLY INTRODUCTION OF ENTERAL FEEDS (COMPARISON 1)
Necrotising enterocolitis (Outcome 1.1: four trials): Meta-analysis of data from Davey 1994, Ostertag 1986, Leaf 2010, and Karagianni 2010 did not detect a statistically significant effect: typical RR 0.89 (95% CI 0.58 to 1.37); typical RD -0.01 (95% CI -0.07 to 0.04). There was no statistical evidence of heterogeneity in this meta-analysis (Figure 1).
|Figure 1. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.1 Necrotising enterocolitis.|
Mortality (Outcome 1.2: four trials): Meta-analysis of data from Davey 1994, Ostertag 1986, Leaf 2010, and Karagianni 2010 did not detect a statistically significant effect: typical RR 1.03 (0.59, 1.78); typical RD 0.00 (95% CI -0.04 to 0.05). There was no statistical evidence of heterogeneity in this meta-analysis (Figure 2).
|Figure 2. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge.|
Growth (Outcome 1.3: two trials): Davey 1994 did not detect a statistically significant difference in the median time to regain birth weight (13 days for both groups). Khayata 1987 reported no significant difference in the weekly rate of weight gain during the first six weeks after birth: mean difference -1.00 (95% CI -127.4 to 125.4) g/kg.
Long-term growth parameters were not assessed by any of the trials.
Neurodevelopment: None of the trials assessed neurodevelopmental outcomes.
Time to establish full enteral feeding (three trials): Karagianni 2010 (median difference 3 days) and Leaf 2010 (median difference 3 days) both reported that the time to establish full enteral feeding was statistically significantly longer in infants in the delayed introduction group. Davey 1994 did not find a statistically significant difference (median 19 versus 22.5 days after birth).
Time to establish full oral feeding: Not reported by the included trials.
Feed intolerance (Outcome 1.3: two trials): Davey 1994 did not detect a statistically significant difference in the proportion of infants who had gastric residual volumes more than 20% of the preceding feed volume, abdominal distention (daily increment in abdominal girth of at least 2 cm) or enteral feeding interrupted or ceased because of feed intolerance. Karagianni 2010 reported that 15 infants in the delayed group versus 14 in the earlier introduction group had feed intolerance [RR 1.05 (95% CI 0.58 to 1.87); RD 0.02 (-0.19 to 0.22)]. Data from Leaf 2010 have not yet been published but will be included in an update when available.
Incidence of invasive infection (Outcome 1.4: one trial): Leaf 2010 did not detect a statistically significant difference in the: RR 1.20 (95% CI 0.87 to 1.67); RD 0.05 (95% CI -0.04 to 0.14).
Duration of hospital stay (Outcome 1.5: one trial): Davey 1994 did not find a statistically significant difference in the median duration of hospital admission (60 versus 47 days). There was no significant difference in the postmenstrual age at discharge: mean difference 0.90 (95% CI -1.21 to 3.01) weeks. Data from Leaf 2010 have not yet been published but will be included in an update when available.
- Extremely low birth weight or extremely preterm infants: None of the trials included a majority of extremely low birth weight or extremely preterm infants.
- Two trials recruited only infants with intrauterine growth restriction and abnormal flow velocities detected on antenatal Doppler studies (Karagianni 2010; Leaf 2010). Meta-analysis did not detect any statistically significant differences in the incidence of necrotising enterocolitis [typical RR 0.79 (95% CI 0.48 to 1.31; typical RD -0.03 (95% CI -0.09 to 0.13)] or death [typical RR 0.96 (95% CI 0.47 to 1.93); typical RD 0.00 (95% CI -0.05 to 0.04)].
Summary of main results
Five randomised controlled trials in which a total of 600 infants participated have assessed the effect of delaying the introduction of progressive enteral feeds on the risk of necrotising enterocolitis and other short term clinical outcomes in very low birth weight infants. The available data from these trials do not provide evidence that delayed introduction reduces the risk of necrotising enterocolitis or death but the 95% confidence intervals for the pooled estimates of effect are wide. Growth-restricted infants who had delayed introduction of feeds achieved full enteral feeding about three days later than infants who had earlier introduction. Whether this is associated with important clinical adverse consequences such as a higher rate of nosocomial infection secondary to prolonged use of parenteral nutrition or a longer duration of hospital admission is not yet known.
Overall completeness and applicability of evidence
These data are relevant to current practice since the two largest trials (Karagianni 2010; Leaf 2010), in which 488 infants participated, were conducted during the past five years with infants receiving 'modern' perinatal care including exposure to antenatal corticosteroids and exogenous surfactant (interventions which reduce the risk of necrotising enterocolitis or death in this population: Roberts 2006; Seger 2009; Soll 2009; Soll 2010). These trials specifically recruited infants thought to be at higher risk of developing necrotising enterocolitis due to intra-uterine growth-restriction and abnormal fetal circulatory distribution or flow (Stoll 2004; Dorling 2005). This further increases the applicability of the findings since this is the population for which most clinical uncertainty and variation in practice with regard to early feeding strategies exists (Boyle 2004). Previously, this population of infants has been specifically excluded from participating in many trials of early enteral feeding practices (Tyson 2007).
Evidence exists that formula milk feeding increases the risk necrotising enterocolitis (Lucas 1990; Quigley 2007). The risk-benefit balance of enteral feeding strategies may differ between breast milk-fed and formula-fed very low birth weight infants. Currently there are insufficient data to comment on whether there is a differential effect of the timing of the introduction of enteral feeds depending on whether infants received human breast milk versus formula milk. This issue may be clarified when the subgroup data from the largest trial are available (Leaf 2010).
It is also unclear whether the findings can be applied to infants who receive continuous infusion of intragastric feeds, as most of the infants in the included trials received enteral feeds as interval gastric boluses. Randomised controlled trials have reported conflicting findings about the effect on continuous enteral infusion on feed tolerance in very (and especially extremely) low birth weight infants (Premji 2003; Dsilna 2005).
All of the included trials have been undertaken in neonatal care centres in high-income countries. It is unclear how applicable this evidence is to neonatal care practices in middle- and low-income countries. Conservative strategies such as delayed introduction of enteral feeds may confer less nutritional disadvantage in settings where adjunctive parenteral nutrition is readily and safely available. In settings with less technologically-developed healthcare provision where parenteral nutrition is not available and where severe infection (diarrhoea, pneumonia, septicaemia) is much more important cause of mortality and morbidity, the nutritional and immunological advantages of early feeding, particularly with breast milk, may outweigh any risks associated with enteral feeding for very low birth weight infants (Narayanan 1982; de Silva 2004).
Quality of the evidence
The included trials were generally of good methodological quality but, in common with other trials of feeding interventions in this population, it was not possible to mask caregivers and clinical assessors to the nature of the intervention. Although the lack of blinding may have resulted in surveillance and ascertainment biases, this is more likely to have caused an underestimation of the incidence of necrotising enterocolitis in infants whose enteral feeding was delayed. The assessment of abdominal radiographs for signs of necrotising enterocolitis was masked to ensure that the diagnosis of stage II/III necrotising enterocolitis (confirmed by the radiological detection of gas in the bowel wall or portal tract) was not prone to bias. However, since the microbial generation of gas in the bowel wall is substrate dependent, infants who received more enteral milk (substrate) may have been more likely to demonstrate this radiological sign than infants with equally severe bowel disease who had less intraluminal substrate. This "substrate effect" is also more likely to cause under-ascertainment of necrotising enterocolitis in the infants whose enteral feeding was delayed (Tyson 2007).
Potential biases in the review process
The definition of delayed introduction of progressive feeds may vary between different subpopulations of very low birth weight infants who have different empiric risks for developing feed intolerance and necrotising enterocolitis. For example, the effects of enteral feeding are likely to be very different for a mechanical ventilator or inotrope dependent infant of birth weight less than 700 grams compared with a clinically-stable infant of birth weight more than 1400 grams. For this Cochrane review, delayed introduction was defined as later than four days after birth since some observational studies have found the risk of necrotising enterocolitis to be lower when feeds are introduced five to seven days after birth (Patole 2005). For extremely low birth weight or extremely preterm infants, it may be more appropriate to define delayed introduction as more than seven days after birth (or even later). Small intestinal motility is poorly organised before about 28 weeks' gestation resulting in a higher risk of feed intolerance. Additionally, enteral feeds are often delayed in this population because of respiratory or metabolic instability or because of other putative risk factors for necrotising enterocolitis such as the existence of a patent ductus arteriosus, the use of non-steroidal anti-inflammatory agents, or the presence of a umbilical arterial catheter (Boyle 2004).
Implications for practice
The available data from randomised controlled trials do not provide evidence that delaying the introduction of progressive enteral feeds reduces the risk of necrotising enterocolitis, mortality, and other morbidities in very low birth weight infants. However, this finding should be applied cautiously since the lower bounds of the 95% confidence intervals for the pooled estimates of effect are consistent with more than 40% reduction in the risk of necrotising enterocolitis and death in infants who have delayed introduction. Given this level of uncertainty, some clinicians may prefer to continue to use evidence from observational studies that have found that delaying the introduction of progressive enteral feeds is associated with a reduced risk of necrotising enterocolitis to inform their practice.
Implications for research
Further large randomised controlled trials are needed to provide robust evidence to inform this fundamental area of neonatal care. Trials need to be simple and pragmatic and should aim to include participation of extremely low birth weight and extremely preterm infants as well as infants with evidence of compromised intrauterine growth so that subgroup analyses can be planned for these populations at high risk of necrotising enterocolitis. Trials could assess the effects of delayed introduction of progressive enteral feeding preceded either by a period of enteral fasting or trophic feeding. Initial trophic feeding may be preferred given that it is not associated with a statistically significant effect on the risk of necrotising enterocolitis (Bombell 2009).
It is difficult to design a pragmatic trial that will ensure that caregivers and investigators are unaware of the allocated feeding regimen. This lack of blinding may cause surveillance and ascertainment biases that result in over-estimation of the incidence of feed intolerance and necrotising enterocolitis in infants whose feeds are introduced earlier. A priori definition of "feed intolerance" and indications for advancing or interrupting enteral feeding and for investigation of necrotising enterocolitis may help minimise the impact of this source of bias. Given these problems, and since conservative feeding strategies could have competing effects such as increasing the risk of nosocomial infection that influence growth, development and mortality, it is essential that trials are powered and structured to assess these outcomes.
We are grateful to Ms Kate Light (Information Specialist, CRD, University of York) for advice on developing the updated electronic search.
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Index terms
Last assessed as up-to-date: 30 December 2010.
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998
Contributions of authors
Jessie Morgan and Lauren Young updated the search, independently determined the eligibility of identified studies, assessed the methodological quality of the included trials, and extracted the relevant information and data. All authors completed the final review.
Declarations of interest
Medical Subject Headings (MeSH)
*Infant, Very Low Birth Weight; Enteral Nutrition [*methods]; Enterocolitis, Necrotizing [*prevention & control]; Infant, Newborn; Infant, Premature; Parenteral Nutrition; Randomized Controlled Trials as Topic; Time Factors
MeSH check words
* Indicates the major publication for the study