Description of the condition
Necrotising enterocolitis (NEC) is an important cause of morbidity, mortality and neuro-disability in very preterm (< 32 weeks) or very low birth weight (VLBW: < 1500 g) infants. Extremely low birth weight (ELBW: < 1000 g) and extremely preterm (< 28 weeks) infants are at greatest risk (Bisquera 2002; Holman 2006; Rees 2007; Berrington 2012). 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 preterm or VLBW infants who develop NEC have received enteral milk feeds. Evidence exists that feeding with artificial formula rather than human milk increases the risk (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 NEC (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 NEC (Patole 2005; Hay 2008).
Why it is important to do this review
In current clinical practice, the introduction of progressive enteral feeds for very preterm or VLBW infants is often preceded by a period of enteral fasting or "minimal enteral nutrition" (Boyle 2004; Patole 2004; Hay 2008; Klingenberg 2012). 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 NEC should not be considered in isolation of these other potential clinical outcomes when determining feeding policies and practice for very preterm or VLBW 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 minimal enteral nutrition levels. We address the effect of minimal enteral nutrition, 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 in another Cochrane review (Bombell 2009).
To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants.
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials or cluster-randomised trials.
Types of participants
VLBW (< 1500 g) or very preterm (< 32 weeks) newborn infants.
Types of interventions
Delayed introduction (> 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 minimal enteral nutrition levels (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. NEC 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 by a diagnosis confirmed at surgery or autopsy (Walsh 1986).
2. All-cause mortality during the neonatal period and prior to hospital discharge.
(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 10th percentile for the index population's distribution) assessed at intervals from six months of age.
(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 (http://neonatal.cochrane.org/).
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), and CINAHL (1982 to April 2013) 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 for Systematic Reviews of Interventions (Higgins 2011). No language restrictions were 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 to 2012), the European Society for Pediatric Research (1995 to 2012), the UK Royal College of Paediatrics and Child Health (2000 to 2012), and the Perinatal Society of Australia and New Zealand (2000 to 2012). 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 (http://neonatal.cochrane.org/).
Selection of studies
Two review authors screened the title and abstract of all studies identified by the above search strategy. We assessed the full text of any potentially eligible reports 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. We discussed any disagreements until consensus was achieved. We contacted the investigators for further information if data from the trial reports were insufficient.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the 'Risk of bias' tables:
- Sequence generation: We categorised the method used to generate the allocation sequence as:
- low risk: any random process e.g. random number table; computer random number generator;
- high risk: any non random process e.g. odd or even date of birth; patient case-record number);
- Allocation concealment: We categorised the method used to conceal the allocation sequence as:
- low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;
- high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;
- Blinding: We assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:
- low risk;
- high risk;
- Incomplete outcome data: 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:
- low risk: < 20% missing data;
- high risk: > 20% missing data;
Measures of treatment effect
We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CI). We planned to determine the number needed to treat for benefit or harm for any statistically significant differences 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-effect model in RevMan 5 (RevMan 2011) for meta-analysis.
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
- trials in which most infants were exclusively formula-fed;
- trials in which most infants were at least partially fed with human milk (maternal or donor);
- trials in which most participants were of ELBW (< 1000 g) or extremely preterm (< 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
We identified 13 reports for screening.
Seven trials fulfilled the review eligibility criteria: Ostertag 1986; Khayata 1987; Davey 1994; Karagianni 2010; Pérez 2011; Leaf 2012; Abdelmaaboud 2012 (see table 'Characteristics of included studies').
A total of 964 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; VLBW infants assessed to be at high risk of developing NEC (N = 38).
- Khayata 1987; VLBW infants (N = 12).
- Davey 1994; Clinically stable preterm infants of birth weight < 2000 g who had a low umbilical artery catheter in situ (N = 62). Since most participants were of birth weight < 1500 g or gestational age < 32 weeks, a consensus decision to include the trial was made.
The four more recent and larger trials were performed within the past 10 years.
- Karagianni 2010: single-centre study in Greece, infants < 35 weeks' gestation with a birth weight < 10th percentile and evidence of abnormal fetal blood flow patterns on Doppler ultrasound of the umbilical artery (N = 84).
- Leaf 2012: 54-centre trial in the UK and Ireland, infants i) < 35 weeks' gestation, (ii) birth weight < 10th percentile, and (iii) evidence of abnormal fetal blood flow patterns on Doppler ultrasound studies (N = 404). Since most participants were of birth weight < 1500 g, a consensus decision to include the trial was made.
- Pérez 2011: single centre in Columbia, very preterm or VLBW infants (N = 239).
- Abdelmaaboud 2012: single centre in Qatar, preterm infants with intrauterine growth restriction and abnormal Doppler flow patterns on ultrasound of the umbilical artery (N = 125). Since most participants were of birth weight < 1500 g, a consensus decision to include the trial was made.
- "Early" feeding varied from day one to four after birth.
In five trials infants received either breast milk, artificial formula or a combination of the two (Davey 1994; Karagianni 2010; Pérez 2011; Leaf 2012, Abdelmaaboud 2012). Only formula-fed infants participated in two trials (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. In Ostertag 1986, infants were initially fed with a sterile water infusion slowly progressing to a 2.5% dextrose solution followed by half-strength formula. They reached full-strength formula milk seven days after initiating enteral feeds.
All of the trial protocols, except that of the smallest trial (Khayata 1987), specified criteria and indications for advancing (daily increments of 15 to 20 mL/kg) or interrupting enteral feed (for example, residual gastric contents not > 3 to 5 mL or one-third to one-half of the previous feed volume, frequent vomiting, abdominal distention, or detection of blood in the stools).
Six of the trials reported the incidence of NEC (Bell stage II/III: confirmed radiologically, or at surgery or autopsy). The other reported outcomes included mortality, time to establish full enteral feeding, growth and duration of hospital stay. Only one trial reported the incidence of invasive infection (Leaf 2012).
Risk of bias in included studies
|Figure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
The smallest trial (N = 12) was reported in abstract form only and methodological details were not described (Khayata 1987).
The other trials had various methodological weaknesses. In three trials, methods to ensure adequate allocation concealment were not described. None of the trials was able to conceal the feeding strategies from parents, caregivers or clinical investigators. The assessment of abdominal radiographs (for diagnosis of NEC) was masked in three trials and in particular this was conducted well in the largest two studies (Pérez 2011; Leaf 2012). 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
Necrotising enterocolitis (Outcome 1.1: six trials)
Meta-analysis did not detect a statistically significant effect: typical RR 0.92 (95% CI 0.64 to 1.34); typical RD -0.01 (95% CI -0.05 to 0.03). There was no statistical evidence of heterogeneity or funnel plot asymmetry (Figure 2; Figure 3).
|Figure 2. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.1 Necrotising enterocolitis.|
|Figure 3. Funnel plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.1 Necrotising enterocolitis.|
Mortality prior to discharge (Outcome 1.2: five trials)
Meta-analysis did not detect a statistically significant effect: typical RR 1.26 (95% CI 0.78 to 2.01); typical RD 0.02 (95% CI -0.02 to 0.05). There was no statistical evidence of heterogeneity or funnel plot asymmetry (Figure 4; Figure 5).
|Figure 4. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge.|
|Figure 5. Funnel plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge.|
Growth (four trials)
Two studies did not detect a statistically significant difference in the median time to regain birth weight:
- Davey 1994: 13 days for both groups (range not reported).
- Abdelmaaboud 2012: 13 days in the delayed group compared to 14 days in the early introduction group (range not reported).
Long-term growth parameters were not assessed by any of the trials.
None of the trials assessed neurodevelopmental outcomes.
Time to establish full enteral feeding (five trials)
The median time to establish full enteral feeding was longer in infants in the delayed introduction group but the reports did not provide data to allow quantitative synthesis:
- Davey 1994: three days.
- Karagianni 2010: three days.
- Pérez 2011: four days.
- Leaf 2012: three days.
- Abdelmaaboud 2012: two days.
Time to establish full oral feeding
Not reported by any of the trials.
Feed intolerance (Outcome 1.3: two trials)
Meta-analysis of data from Karagianni 2010 and Abdelmaaboud 2012 did not detect a statistically significant difference: typical RR 1.04 (95% CI 0.72 to 1.49); typical RD 0.01 (95% CI -0.12 to 0.14) (Figure 6).
|Figure 6. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.3 Feed intolerance.|
Davey 1994 did not detect a statistically significant difference but the report did not provide data to allow quantitative synthesis.
Incidence of invasive infection (Outcome 1.4: one trial)
Leaf 2012 did not detect a statistically significant difference: RR 1.25 (95% CI 0.93 to 1.68); RD 0.07 (95% CI -0.02 to 0.16).
Duration of hospital stay (Outcome 1.5: four trials)
Meta-analysis of data from two trials did not detect a statistically significant effect: MD 1.24 (95% CI -0.67 to 3.14) days (Davey 1994; Pérez 2011). Another two trials did not detect a statistically significant effect but the reports did not provide data to allow quantitative synthesis (Abdelmaaboud 2012; Leaf 2012).
- Trials in which most infants were at least partially fed with human milk (maternal or donor): subgroup data not available.
- ELBW or extremely preterm infants: none of the trials recruited predominantly ELBW or extremely preterm infants.
- Three trials recruited only infants with intrauterine growth restriction and abnormal flow velocities detected on antenatal Doppler studies (Karagianni 2010; Leaf 2012, Abdelmaaboud 2012). Meta-analysis did not detect any statistically significant differences in the incidence of NEC (typical RR 0.87 (95% CI 0.54 to 1.41); typical RD -0.01 (95% CI -0.06 to 0.03)) (Figure 2) or death (typical RR 1.06 (95% CI 0.55 to 2.05); typical RD 0.00 (95% CI -0.04 to 0.05)) (Figure 4).
Summary of main results
Seven randomised controlled trials in which a total of 964 infants participated have assessed the effect of delaying the introduction of progressive enteral feeds on the risk of developing NEC and other adverse outcomes in very preterm or VLBW infants. The data from these trials do not provide evidence that delayed introduction affects the risk of NEC or death. Infants who had delayed introduction of feeds achieved full enteral feeding about one to 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 remains unclear.
Overall completeness and applicability of evidence
These data are relevant to current practice since the four largest trials (Karagianni 2010; Pérez 2011; Leaf 2012; Abdelmaaboud 2012), in which 852 infants participated, were conducted during the past 10 years with infants receiving 'modern' perinatal care including exposure to antenatal corticosteroids and exogenous surfactant, interventions which reduce the risk of NEC or death in this population (Roberts 2006; Seger 2009; Soll 2009; Soll 2010). Three of these trials specifically recruited infants thought to be at higher risk of developing NEC due to intra-uterine growth-restriction and abnormal fetal circulatory distribution or flow. This 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 artificial formula feeding increases the risk NEC (Quigley 2007). The risk-benefit balance of enteral feeding strategies may differ between human milk-fed and formula-fed very preterm or VLBW 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. This issue may be clarified when the subgroup data from the largest trial are available (Leaf 2012).
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 2011).
All of the included trials were undertaken in neonatal care centres in middle- or high-income countries. It is unclear how applicable this evidence is to neonatal care practices in 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 a 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 preterm or VLBW infants (Narayanan 1982; de Silva 2004).
Quality of the evidence
The included trials were generally of reasonable 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 NEC in infants whose enteral feeding was delayed. The assessment of abdominal X-rays was masked in three studies to ensure that the diagnosis of stage II/III NEC (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 NEC 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 preterm or VLBW infants who have different empiric risks for developing feed intolerance and NEC. The effects of enteral feeding are likely to be very different for a mechanical ventilator or inotrope-dependent infant of birth weight < 700 g compared with a clinically-stable infant of birth weight > 1400 g. For this Cochrane review, delayed introduction was defined as later than four days after birth since some observational studies have found the risk of NEC to be lower when feeds are introduced five to seven days after birth (Patole 2005). For ELBW 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 NEC 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 beyond four days after birth affects the risk of NEC, mortality, and other morbidities in very preterm or VLBW infants. Delaying the introduction of progressive enteral feeds may result in two to four days delay in establishing full enteral feeds but the long-term clinical importance of these effects is unclear. Subgroup analyses of trials in which participating infants had evidence of intra-uterine growth restriction or abnormal circulatory distribution or flow did not find any statistically significant effects. However, only limited data are available on the effect of this intervention on outcomes for extremely preterm or ELBW infants. Although current practice tends to favour a conservative approach to enteral feeding in these populations, it also needs to be considered that there are other possible consequences of delayed introduction of enteral feeds such as prolonging the use of parenteral nutrition that may be associated with adverse clinical outcomes.
Implications for research
Further randomised controlled trials could provide more precise estimates of the effects of delaying the introduction of progressive enteral feeding on important outcomes for very preterm or VLBW infants. Trials should aim to ensure the participation of ELBW and extremely preterm infants so that subgroup analyses can be planned for these populations at high risk of NEC. Masking caregivers and investigators to the nature of this intervention is unlikely to be possible. Since the unblinded evaluation of feed intolerance and NEC is subject to surveillance and ascertainment biases, trials could aim to assess more objective outcomes, principally mortality and long-term growth and development. Furthermore, since conservative feeding strategies may result in other "competing outcomes" such as invasive infection that may affect on long-term survival and neuro-disability rates, it is essential that trials are powered and structured to assess these outcomes.
We gratefully acknowledge the contributions of Drs Kennedy, Tyson, Chamnanvanakij, and Bombell to previous iterations of this review.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Last assessed as up-to-date: 26 April 2013.
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
Sources of support
- Centre for Reviews and Dissemination, Hull York Medical School, UK.
- National Institute for Health Research, UK.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.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
Medical Subject Headings (MeSH)
*Infant, Low Birth Weight; *Infant, Premature; Enteral Nutrition [*methods]; Enterocolitis, Necrotizing [*prevention & control]; Infant, Extremely Low Birth Weight; Infant, Extremely Premature; Infant, Newborn; Infant, Very Low Birth Weight; Parenteral Nutrition; Randomized Controlled Trials as Topic; Time Factors
MeSH check words
* Indicates the major publication for the study