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Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants

  1. Jessie Morgan,
  2. Lauren Young,
  3. William McGuire*

Editorial Group: Cochrane Neonatal Group

Published Online: 31 MAY 2013

Assessed as up-to-date: 26 APR 2013

DOI: 10.1002/14651858.CD001970.pub4


How to Cite

Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 5. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub4.

Author Information

  1. Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK

*William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD, UK. William.McGuire@hyms.ac.uk.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 31 MAY 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

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).

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

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

 

Primary outcomes

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.

 

Secondary outcomes

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 10th 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 (http://neonatal.cochrane.org/).

 

Electronic searches

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.

We searched ClinicalTrials.gov and Current Controlled Trials for completed or ongoing trials.

 

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:

  1. Sequence generation: We categorised the method used to generate the allocation sequence as:
    1. low risk: any random process e.g. random number table; computer random number generator;
    2. high risk: any non random process e.g. odd or even date of birth; patient case-record number);
    3. unclear.
  2. Allocation concealment: We categorised the method used to conceal the allocation sequence as:
    1. low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;
    2. high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;
    3. unclear.
  3. Blinding: We assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:
    1. low risk;
    2. high risk;
    3. unclear.
  4. 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:
    1. low risk: < 20% missing data;
    2. high risk: > 20% missing data;
    3. unclear.

 

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.

 

Data synthesis

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:

  1. trials in which most infants were exclusively formula-fed;
  2. trials in which most infants were at least partially fed with human milk (maternal or donor);
  3. trials in which most participants were of ELBW (< 1000 g) or extremely preterm (< 28 weeks);
  4. 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.

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Description of studies

We identified 13 reports for screening.

 

Included studies

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').

 

Population

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.

 

Interventions/comparisons

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).

 

Outcomes

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).

 

Excluded studies

We excluded six studies after full text screening (Higgs 1974; Glass 1984; LaGamma 1985; Wilson 1997; Weiler 2006; Said 2008) (see table Characteristics of excluded studies).

 

Risk of bias in included studies

Quality assessments are described in the table 'Characteristics of included studies' and Figure 1.

 FigureFigure 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

 

PRIMARY OUTCOMES

 
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).

 FigureFigure 2. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.1 Necrotising enterocolitis.
 FigureFigure 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).

 FigureFigure 4. Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge.
 FigureFigure 5. Funnel plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge.

 

SECONDARY OUTCOMES

 
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).

Two trials did not detect statistically significant differences in the rate of weight gain but the reports did not provide data to allow quantitative synthesis (Khayata 1987; Pérez 2011).

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 (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:

 
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).

 FigureFigure 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).

 
Subgroup analyses

  1. Two trials only recruited exclusively formula-fed infants (Khayata 1987; Ostertag 1986). Only Ostertag 1986 reported the effect on NEC (RR 1.08 (95% CI 0.40 to 2.94; RD 0.02 (95% CI -0.27 to 0.31)) or death (RR 1.44 (95% CI 0.57 to 3.61); RD 0.12 (95% CI -0.18 to 0.42)).
  2. Trials in which most infants were at least partially fed with human milk (maternal or donor): subgroup data not available.
  3. ELBW or extremely preterm infants: none of the trials recruited predominantly ELBW or extremely preterm infants.
  4. 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).

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

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).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

 

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.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

We gratefully acknowledge the contributions of Drs Kennedy, Tyson, Chamnanvanakij, and Bombell to previous iterations of this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
Download statistical data

 
Comparison 1. Delayed versus early introduction of progressive enteral feeding

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Necrotising enterocolitis6Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 All trials
6950Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.64, 1.34]

    1.2 Trials in which participants were infants with intrauterine growth restriction and/or abnormal antenatal Doppler flow velocities
3613Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.54, 1.41]

 2 Mortality prior to discharge5Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 All trials
5825Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.78, 2.01]

    2.2 Trials in which participants were infants with intrauterine growth restriction and/or abnormal antenatal Doppler flow velocities
2488Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.55, 2.05]

 3 Feed intolerance2206Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.72, 1.49]

 4 Incidence of invasive infection1397Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.93, 1.68]

 5 Duration of hospital admission (postmenstrual weeks at discharge)2286Mean Difference (IV, Fixed, 95% CI)1.24 [-0.67, 3.14]

 6 Subgroup analysis with infants < 29 weeks' gestation: mortality186Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.41, 3.81]

 7 Subgroup analysis of infants < 29 weeks' gestation: incidence of necrotising enterocolitis186Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.43, 2.54]

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Last assessed as up-to-date: 26 April 2013.


DateEventDescription

26 April 2013New citation required but conclusions have not changedUpdated search in April 2013 identified two new trials for inclusion in this review update.

26 April 2013New search has been performedThis updates the review "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" (Morgan 2011).



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998


DateEventDescription

13 January 2011New search has been performedThis updates the review "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 2, 2008 (Bombell 2008).

Updated search includes three new trials (Ostertag 1986; Karagianni 2010; Leaf 2012).

New authorship for this review update.

13 January 2011New citation required and conclusions have changedThe addition of new trial data has increased the total number of participating infants to 600 and modified the implications for practice and research.

2 February 2008New search has been performedThis updates the review "Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 1, 2000 (Kennedy 2000).

The title has been changed to "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" and has a new authorship of Sarah Bombell and William McGuire. Changes made to the original protocol are outlined below:

1. Introduction of progressive enteral feeds is defined as feed volumes more than 24 ml/kg/day (1 ml/kg/hour).
2. The population has been restricted to very low birth weight and very preterm infants
3. Subgroup analyses of extremely low birth weight and extremely preterm infants, and infants with evidence of intrauterine growth restriction or absent or reversed end-diastolic flow velocities in Doppler studies of the fetal aorta or umbilical artery were prespecified.

Search updated December 2007. No new trials were included, but one on-going trial was identified.

The findings and implications for practice and research of the review have not changed overall.

11 January 2008AmendedConverted to new review format.



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms

None known.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. What's new
  11. History
  12. Contributions of authors
  13. Declarations of interest
  14. Sources of support
  15. Index terms
 

Internal sources

  • Centre for Reviews and Dissemination, Hull York Medical School, UK.

 

External sources

  • 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

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Abdelmaaboud 2012 {published data only}
  • Abdelmaaboud M, Mohammed A. A randomized controlled trial on early versus late minimal enteral feeding in preterm growth-restricted neonates with abnormal antenatal Doppler studies. Journal of Neonatal-Perinatal Medicine 2012;5:1-8.
Davey 1994 {published data only (unpublished sought but not used)}
Karagianni 2010 {published data only}
  • Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T, Chatziioannidis E, et al. Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal Doppler results. American Journal of Perinatology 2010;27:367-73.
Khayata 1987 {published data only (unpublished sought but not used)}
  • Khayata S, Gutcher G, Bamberger J, Heimler R. Early versus late feeding of low birth weight (LBW) infants: Effect on growth and hyperbilirubinemia. Pediatric Research 1987;21:431A.
Leaf 2012 {published data only}
  • Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Brocklehurst P. ADEPT - Abnormal Doppler Enteral Prescription Trial. BMC Pediatrics 2009;9:63.
  • Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Brocklehurst P. When should feeds be started in the high risk preterm infant? The Abnormal Doppler Enteral Prescription Trial (ADEPT). E-PAS20101670.7. 2010.
  • Leaf A,  Dorling J,  Kempley S,  McCormick K,  Mannix P, Brocklehurst P. Abnormal Doppler enteral prescription trial study: the results of a trial of feeding in a high risk group of premature babies. Archives of Disease in Childhood Fetal and Neonatal Edition 2010;95:Fa9.
  • Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Linsell L, et al on behalf of ADEPT Clinical Investigators Group. Early or delayed enteral feeding for preterm growth-restricted infants: a randomized trial. Pediatrics 2012;129:1-9.
Ostertag 1986 {published and unpublished data}
  • Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL. Early enteral feeding does not affect the incidence of necrotizing enterocolitis. Pediatrics 1986;77:275-80.
Pérez 2011 {published data only}
  • Pérez LA, Pradilla GL, Díaz G, Bayter SM. Necrotising enterocolitis among preterm newborns with early feeding [Incidencia de enterocolitis necrosante en niños prematuros alimentados precozmente]. Biomédica 2011;31:485-91.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Glass 1984 {published data only}
  • Glass EJ, Hume R, Lang MA, Forfar JO. Parenteral nutrition compared with transpyloric feeding. Archives of Disease in Childhood 1984;59:131-5.
Higgs 1974 {published data only}
  • Higgs SC, Malan AF, DeV Heese H. A comparison of oral feeding and total parenteral nutrition in infants of very low birthweight. South African Medical Journal 1974;48:2169-73.
LaGamma 1985 {published data only}
  • LaGamma EF, Ostertag S, Birenbaum H. Failure of delayed oral feedings to prevent necrotizing enterocolitis. American Journal of Diseases of Children 1985;139:385-9.
Said 2008 {published data only}
  • Said H, Elmetwally D, Said N. Randomized controlled trial of early versus late enteral feeding in prematurely born infants with firth weight ≤ 1200 grams. Kasr El Aini Medical Journal 2008;14:1-10.
Weiler 2006 {published data only}
  • Weiler HA, Fitzpatrick-Wong SC, Chellenberg JM, Fair DE, McCloy UR, Veitch RR, et al. Minimal enteral feeding within 3 d of birth in prematurely born infants with birth weight < 1200g improves bone mass by term age. American Journal of Clinical Nutrition 2006;83:155-62.
Wilson 1997 {published data only}
  • Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA. Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants. Archives of Disease in Childhood 1997;77:F4-11.

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Bernstein 2000
  • Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A. Morbidity and mortality among very-low-birth-weight neonates with intrauterine growth restriction. The Vermont Oxford Network. American Journal of Obstetrics and Gynecology 2000;182:198-206.
Berrington 2012
  • Berrington JE, Hearn RI, Bythell M, Wright C, Embleton ND. Deaths in preterm infants: changing pathology over 2 decades. The Journal of Pediatrics 2012;160:49-53. [PUBMED: 21868028]
Berseth 1990
Bisquera 2002
Bombell 2009
Boyle 2004
  • Boyle EM, Menon G, Elton R, McIntosh N. Variation in feeding practice in preterm and low birth weight infants in Scotland. Early Human Development 2004;77:125-6.
Brown 1978
  • Brown EG, Sweet AY. Preventing necrotizing enterocolitis in neonates. JAMA 1978;240:2452-4.
Burrin 2002
de Silva 2004
  • de Silva A, Jones PW, Spencer SA. Does human milk reduce infection rates in preterm infants? A systematic review. Archives of Disease in Childhood Fetal and Neonatal Edition 2004;89:509-13.
Dorling 2005
  • Dorling J, Kempley S, Leaf A. Feeding growth restricted preterm infants with abnormal antenatal Doppler results. Archives of Disease in Childhood Fetal and Neonatal Edition 2005;90:359-63.
Flidel-Rimon 2004
  • Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES. Early enteral feeding and nosocomial sepsis in very low birthweight infants. Archives of Disease in Childhood Fetal and Neonatal Edition 2004;89:289-92.
Flidel-Rimon 2006
Garite 2004
  • Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction increases morbidity and mortality among premature neonates. American Journal of Obstetrics and Gynecology 2004;191:481-7.
Hartel 2009
  • Hartel C, Haase B, Browning-Carmo K, Gebauer C, Kattner E, Kribs A, et al. Does the enteral feeding advancement affect short-term outcomes in very low birth weight infants?. Journal of Pediatric Gastroenterology and Nutrition 2009;48:464-70.
Hay 2008
Henderson 2009
  • Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral feeding regimens and necrotising enterocolitis in preterm infants: a multicentre case-control study. Archives of Disease in Childhood. Fetal and Neonatal Edition 2009;94:F120-3.
Hershkovitz 2000
Higgins 2011
  • Higgins JPT, Green S, editors. 2011. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration,. Available from www.cochrane-handbook.org 2011.
Holman 2006
Kamoji 2008
Klingenberg 2012
  • Klingenberg C, Embleton ND, Jacobs SE, O'Connell LA, Kuschel CA. Enteral feeding practices in very preterm infants: an international survey. Archives of Disease in Childhood. Fetal and Neonatal Edition 2012;97:F56-61. [PUBMED: 21856644]
Narayanan 1982
Patole 2004
  • Patole S, Muller R. Enteral feeding of preterm neonates: a survey of Australian neonatologists. Journal of Maternal-Fetal & Neonatal Medicine 2004;16:309-14.
Patole 2005
  • 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. Archives of Disease in Childhood Fetal and Neonatal Edition 2005;90:147-51.
Premji 2011
Quigley 2007
Rees 2007
  • Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes of neonates with medically and surgically treated necrotizing enterocolitis. Archives of Disease in Childhood Fetal and Neonatal Edition 2007;92:193-8.
RevMan 2011
  • Nordic Cochrane Centre. The Cochrane Collaboration. Review Manager (RevMan). 5.1. Copenhagen: Nordic Cochrane Centre. The Cochrane Collaboration, 2011.
Roberts 2006
Seger 2009
Soll 2009
Soll 2010
Stoll 2004
  • Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR, Vohr B, et al. Neurodevelopmental and growth impairment among extremely low-birth-weight infants with neonatal infection. JAMA 2004;292:2357-65.
Tyson 2007
Uauy 1991
  • Uauy RD, Fanaroff AA, Korones SB, Phillips EA, Phillips JB, Wright LL. Necrotizing enterocolitis in very low birth weight infants: biodemographic and clinical correlates. National Institute of Child Health and Human Development Neonatal Research Network. Journal of Pediatrics 1991;119:630-8.
Walsh 1986

References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Characteristics of studies
  17. References to studies included in this review
  18. References to studies excluded from this review
  19. Additional references
  20. References to other published versions of this review
Bombell 2008
Kennedy 2005
  • Kennedy KA, Tyson JE, Chamnanvanikij S. Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants. Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI: 10.1002/14651858.CD001970.pub2]
Morgan 2011
  • Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD001970.pub3]