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

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Authors

Jessie Morgan1, Lauren Young1, William McGuire1

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK [top]

Citation example: 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 2014, Issue 12. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub5.

Contact person

William McGuire

Hull York Medical School & Centre for Reviews and Dissemination, University of York
York
Y010 5DD
UK

E-mail: William.McGuire@hyms.ac.uk

Dates

Assessed as Up-to-date: 06 October 2014
Date of Search: 03 October 2014
Next Stage Expected: 03 October 2016
Protocol First Published: Issue 4, 1998
Review First Published: Issue 4, 1998
Last Citation Issue: Issue 12, 2014

What's new

Date / Event Description
03 October 2014
Updated

This updates the review "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" (Morgan 2013b).

03 October 2014
New citation: conclusions not changed

Updated search in September 2014 identified two new trials for inclusion in this review update (Armanian 2013; Arnon 2013).

History

Date / Event Description
13 January 2011
New citation: conclusions changed

The addition of new trial data has increased the total number of participating infants to 600 and modified the implications for practice and research.

13 January 2011
Updated

This 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.

02 February 2008
Updated

This 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 2008
Amended

Converted to new review format.

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Abstract

Background

The introduction of enteral feeds for very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW; less than 1500 g) infants is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks.

Objectives

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.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014), CINAHL (1982 to September 2014), conference proceedings and previous reviews.

Selection criteria

We included randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants.

Data collection and analysis

Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment effects in the individual trials and reported the risk ratio (RR) and risk difference for dichotomous data and mean difference for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of heterogeneity in sensitivity analyses.

Main results

We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks' gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than four to seven days after birth and early introduction as four days or less after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical RR 0.93, 95% CI 0.64 to 1.34; 8 trials; 1092 infants) or all-cause mortality (typical RR 1.18, 95% CI 0.75 to 1.88; 7 trials; 967 infants). Four of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials found no statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median differences two to four days).

Authors' conclusions

The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth-restricted infants. Delaying the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further randomised controlled trials in this population may be warranted.

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Plain language summary

No evidence that delayed introduction of progressive enteral feeds prevents necrotising enterocolitis in very low birth weight infants

Background

Very preterm (less than 32 weeks' gestation) or very low birth weight (less than 1500 g) infants are at risk of developing a severe bowel disorder called necrotising enterocolitis, where parts of the bowel become inflamed and start to die. One possible way to prevent this condition is to delay the introduction of milk feeds until several days (or longer) after birth.

Study characteristics

We search scientific databases for clinical trials assessing the effect of delayed (more than four days after birth) versus earlier introduction of progressive enteral feeds (where breast or formula milk is fed directly by a tube into the stomach) on the incidence of necrotising enterocolitis, death and general health in very low birth weight infants. The evidence is current to September 2014.

Key results

We found nine trials with 1106 infants that assessed the effect of delayed rather than early introduction of milk feeds for very preterm or very low birth weight infants. Data from these trials did not provide any evidence that delaying enteral feeding reduces the risk of necrotising enterocolitis.

Quality of the evidence

The included trials were generally of reasonable methodological quality but, in common with other trials of feeding interventions in infants, it was not possible to mask carers and clinical assessors to the given treatment.

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Background

Description of the condition

Necrotising enterocolitis (NEC) is an important cause of morbidity, mortality and neuro-disability in very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW: less than 1500 g) infants. Extremely low birth weight (ELBW: less than 1000 g) and extremely preterm (less than 28 weeks' gestation) 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 of developing NEC (Quigley 2014). 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 until beyond about four 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 focused 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 addressed 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 (Morgan 2013a).

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Objectives

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.

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Methods

Criteria for considering studies for this review

Types of studies

Randomised or quasi-randomised controlled trials or cluster-randomised trials.

Types of participants

VLBW (less than 1500 g) or very preterm (less than 32 weeks' gestation) newborn infants.

Types of interventions

Delayed introduction (four or more days after birth) of progressive enteral feeds versus earlier introduction of enteral feeds. We defined progressive enteral feeding 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:
    1. abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen;
    2. abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both);
    3. blood in stool;
    4. 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
  1. Growth:

    1. 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);
    2. long-term growth: weight, height or head circumference (with or without proportion of infants who remain below the 10th percentile for the index population's distribution) assessed at intervals from six months of age.
  2. Neurodevelopment:
    1. 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 was analysed individually as well as part of the composite outcome;
    2. neurodevelopmental scores in survivors aged 12 months or greater measured using validated assessment tools;
    3. cognitive and educational outcomes in survivors aged more than five years old.
  3. Time to establish full enteral feeding (independently of parenteral nutrition).
  4. Time to establish oral feeding (independently of parenteral nutrition or enteral tube feeding, or both).
  5. Feed intolerance (defined as a requirement to cease enteral feeds).
  6. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine or from a normally sterile body space.
  7. Duration of hospital stay (days).

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group (neonatal.cochrane.org/ External Web Site Policy).

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE (1980 to September 2014) and CINAHL (1982 to September 2014) 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]. We limited the search outputs with the relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We applied no language restrictions.

We searched ClinicalTrials.gov (clinicaltrials.gov) and Current Controlled Trials (www.controlled-trials.com/ External Web Site Policy) 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 2014), the European Society for Pediatric Research (1995 to 2014), the UK Royal College of Paediatrics and Child Health (2000 to 2014) and the Perinatal Society of Australia and New Zealand (2000 to 2013). 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 (neonatal.cochrane.org/ External Web Site Policy).

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 excluded those studies that did not meet all of the inclusion criteria. We discussed any disagreements until we achieved consensus.

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 we reached consensus. 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 (neonatal.cochrane.org/ External Web Site Policy). We requested additional information from the trial authors 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, participant case-record number);
    3. unclear risk.
  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 (e.g. open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    3. unclear risk.
  3. Blinding: we assessed blinding of participants, clinicians and carers, and outcome assessors separately for different outcomes and categorised the methods as:
    1. low risk;
    2. high risk;
    3. unclear risk.
  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: less than 20% missing data;
    2. high risk: 20% or greater missing data;
    3. unclear risk.

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 an additional beneficial outcome (NNTB) or additional harmful outcome (NNTH) for any statistically significant differences in the RD.

Unit of analysis issues

The unit on analysis was the participating infant in individually randomised trials and the neonatal unit (or sub-unit) for cluster-randomised trials.

Assessment of heterogeneity

If we included more than one trial 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 we detected substantial (I2 greater than 50%) heterogeneity, we explored the possible causes (e.g. differences in study design, participants, interventions or completeness of outcome assessments) in sensitivity analyses.

Data synthesis

We used the fixed-effect model in Review Manager 5 for meta-analysis (RevMan 2011).

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 (less than 1000 g) or extremely preterm (less than 28 weeks' gestation);
  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.

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Results

Description of studies

We identified 13 reports for screening.

Included studies

Nine trials fulfilled the review eligibility criteria: Ostertag 1986; Khayata 1987; Davey 1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013 (see Characteristics of included studies table).

Population

A total of 1106 infants participated in the included trials.

The three smallest trials were undertaken in neonatal care centres in North America during the 1980s and early 1990s.

  1. Ostertag 1986: 38 VLBW infants assessed to be at high risk of developing NEC.
  2. Khayata 1987: 12 VLBW infants.
  3. Davey 1994: 62 clinically stable preterm infants of birth weight less than 2000 g who had a low umbilical artery catheter in situ. Since most participants were of birth weight less than 1500 g or gestational age less than 32 weeks, we made a consensus decision to include the trial.

The six more recent trials were performed in the 2000s to 2010s.

  1. Karagianni 2010: single-centre study in Greece, 84 infants less than 35 weeks' gestation with a birth weight less than 10th percentile and evidence of abnormal fetal blood flow patterns on Doppler ultrasound of the umbilical artery.
  2. Pérez 2011: single-centre study in Columbia, 239 very preterm or VLBW infants.
  3. Leaf 2012: 54-centre trial in the UK and Ireland, 404 infants (a) less than 35 weeks' gestation, (b) birth weight less than 10th percentile and (c) evidence of abnormal fetal blood flow patterns on Doppler ultrasound studies. Since most participants were of birth weight less than 1500 g, we made a consensus decision to include the trial.
  4. Abdelmaaboud 2012: single-centre study in Qatar, 125 preterm infants with intrauterine growth restriction and abnormal Doppler flow patterns on ultrasound of the umbilical artery. Since most participants were of birth weight less than 1500 g, we made a consensus decision to include the trial.
  5. Armanian 2013: single-centre study in Iran, 82 VLBW infants.
  6. Arnon 2013: single-centre study in Israel, 60 small for gestation age preterm infants. Since most participants were of birth weight less than 1500 g, we made a consensus decision to include the trial.
Interventions/comparisons
  1. Eight trials defined 'delayed' introduction of enteral feeds as later than day four to seven after birth (Ostertag 1986; Davey 1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013) and one trial defined it as day 10 after birth (Khayata 1987).
  2. 'Early' feeding varied from day one to four after birth.

In seven trials, infants received breast milk, artificial formula or a combination of the two (Davey 1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013). In two trials, infants received only formula-feed (Ostertag 1986; Khayata 1987). Infants received enteral feeds by gavage at one- or two-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 30 mL/kg) or interrupting enteral feed (e.g. residual gastric contents not greater than 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

Eight of the trials reported the incidence of NEC (confirmed radiologically, or at surgery or autopsy) (Ostertag 1986; Davey 1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013). The other reported outcomes included mortality, time to establish full enteral feeding, growth and duration of hospital stay. Only two trials reported the incidence of invasive infection (Leaf 2012; Arnon 2013).

Excluded studies

We excluded eight studies after full-text screening (Higgs 1974; Glass 1984; LaGamma 1985; Wilson 1997; Weiler 2006; Said 2008; Sanghvi 2013; Chetry 2014) (see Characteristics of excluded studies table).

Risk of bias in included studies

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

The smallest trial (12 infants) was reported in abstract form only and methodological details were not described (Khayata 1987).

The other trials had various methodological weaknesses. In five trials, methods to ensure adequate allocation concealment were not described. None of the trials concealed the feeding strategies from parents, carers or clinical investigators. 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)

Meta-analysis did not detect a statistically significant effect (typical RR 0.93, 95% CI 0.64 to 1.34; typical RD -0.01, 95% CI -0.04 to 0.03; 8 trials; 1092 infants). There was no statistical evidence of heterogeneity (Figure 2).

Mortality prior to discharge (Outcome 1.2)

Meta-analysis did not detect a statistically significant effect (typical RR 1.18, 95% CI 0.75 to 1.88; typical RD 0.01, 95% CI -0.02 to 0.04; 7 trials, 967 infants). There was no statistical evidence of heterogeneity (Figure 3).

Secondary outcomes

Growth

Two trials did not detect a statistically significant difference in the median time to regain birth weight:

  1. Davey 1994: 13 days for both groups (range not reported; 62 infants);
  2. Abdelmaaboud 2012: 13 days in the delayed group compared with 14 days in the early introduction group (range not reported; 125 infants).

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).

None of the other trials reported hospital growth parameters.

None of the trials assessed any long-term (post-hospital discharge) growth parameters.

Neurodevelopment

None of the trials assessed neurodevelopmental outcomes.

Time to establish full enteral feeding

The median time to establish full enteral feeding was longer in the delayed introduction group but the reports did not provide data to allow quantitative synthesis:

  1. Ostertag 1986: not reported;
  2. Khayata 1987: not reported;
  3. Davey 1994: three days;
  4. Karagianni 2010: three days;
  5. Pérez 2011: four days;
  6. Abdelmaaboud 2012: two days;
  7. Leaf 2012: three days;
  8. Armanian 2013: five days;
  9. Arnon 2013: three days.
Time to establish full oral feeding

None of the trials assessed time to establish full oral feeding.

Feed intolerance (Outcome 1.3)

Meta-analysis of data from three trials did not detect a statistically significant difference in feed intolerance (typical RR 0.84, 95% CI 0.62 to 1.15; typical RD -0.06, 95% CI -0.17 to 0.05; 288 infants; Figure 4) (Karagianni 2010; Abdelmaaboud 2012; Armanian 2013).

One trial did not detect a statistically significant difference but the report did not provide data to allow quantitative synthesis (Davey 1994).

None of the other trials reported the incidence of feed intolerance.

Incidence of invasive infection (Outcome 1.4)

Meta-analysis of data from two trials did not detect a statistically significant difference (typical RR 1.27, 95% CI 0.95 to 1.70; typical RD 0.07, 95% CI -0.01 to 0.15; 457 infants) (Leaf 2012; Arnon 2013).

Duration of hospital stay (Outcome 1.5)

Meta-analysis from three trials showed a statistically significant longer duration in the delayed feeding group (MD 2.11 days, 95% CI 0.31 to 3.90; 346 infants; Figure 5). The meta-analysis contained substantial heterogeneity (Chi2 = 7.66; degrees of freedom (df) = 2; P value = 0.02; I2 = 74%).

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 (Ostertag 1986; Khayata 1987). 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; 38 infants) or mortality (RR 1.44, 95% CI 0.57 to 3.61; RD 0.12, 95% CI -0.18 to 0.42; 38 infants).
  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. Four trials recruited only infants with intrauterine growth restriction and abnormal flow velocities detected on antenatal Doppler studies (Karagianni 2010; Abdelmaaboud 2012; Leaf 2012; Arnon 2013). 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; 673 infants; Figure 2) or mortality (typical RR 1.06, 95% CI 0.55 to 2.05; typical RD 0.00, 95% CI -0.04 to 0.05; 548 infants; Figure 3).

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Discussion

Summary of main results

Analyses of data from nine randomised controlled trials with 1106 infants did not provide evidence that delayed introduction of progressive enteral feeds reduced the risk of NEC. The boundaries of the 95% CI for the estimate of effect are consistent with either four fewer or three extra cases of NEC in every 100 infants who had delayed introduction of progressive enteral feeds. Meta-analysis of data from these trials did not indicate an effect on all-cause mortality with the 95% CI boundaries being consistent with either two fewer or four more deaths in every 100 infants who had delayed introduction of progressive enteral feeds. Similarly, pre-specified subgroup meta-analyses showed no effect of delayed introduction of enteral feeds on NEC or mortality in infants with growth restriction or antenatal evidence of absent end-diastolic flow velocities.

Infants who had delayed introduction of feeds achieved full enteral feeding several days later than infants who had earlier introduction. Whether this was 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 most of the included trials were conducted in the 2000s with infants receiving 'modern' antenatal care including exposure to antenatal corticosteroids and exogenous surfactant, interventions that reduce the risk of NEC or death in this population (Roberts 2006; Seger 2009; Soll 2009; Soll 2010). Four of these trials specifically recruited infants thought to be at higher risk of developing NEC due to intrauterine growth restriction and abnormal fetal circulatory distribution or flow. This widens 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 2014). 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.

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 VLBW (and especially ELBW) infants (Premji 2011).

Most of the included trials were undertaken in neonatal care centres in middle- or high-income countries. It is less clear how applicable this evidence is to neonatal care practices in low-income countries. Conservative strategies, such as delayed introduction of enteral feeds, may confer substantial nutritional disadvantage in settings with less technologically developed healthcare provision where adjunctive parenteral nutrition is not readily and safely available. In some low- or middle-income countries 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 1981; de Silva 2004). We identified two feasibility trials undertaken in India in the late 2000s/early 2010s that compared exclusive enteral feeding (no parenteral fluid) from birth with gradual introduction of enteral feeds over several days in VLBW infants with birth weight greater than 1000 g (Sanghvi 2013; Chetry 2014). While these trials were not eligible for inclusion in this review, neither found evidence of an effect on NEC or other adverse outcomes.

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 carers 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 radiographs 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-dependent or inotrope-dependent infant of birth weight less than 700 g compared with a clinically stable infant of birth weight greater than 1400 g. For this Cochrane review, we defined delayed introduction 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. In addition, 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 drugs or the presence of an umbilical arterial catheter (Boyle 2004).

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Authors' conclusions

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 reduces the risk of necrotising enterocolitis (NEC), mortality, and other morbidities in very preterm or very low birth weight (VLBW) infants. Delaying the introduction of progressive enteral feeds may result in several 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 intrauterine 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 extremely low birth weight (ELBW) infants.

Implications for research

Further randomised controlled trials of delayed versus early introduction of progressive enteral feeds could provide more precise estimates of the effects on important outcomes for extremely preterm or ELBW infants. With regard to stable VLBW infants with birth weight greater than 1000 g (or very preterm infants with gestational age 28 to 31 weeks), the key research question is now whether exclusive enteral feeding from birth is better than gradual introduction.

Masking carers 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 long-term survival and neuro-disability rates, it is essential that trials are powered and structured to assess these outcomes.

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Acknowledgements

This report is independent research funded by a UK National Institute of Health Research Grant (NIHR) Cochrane Programme Grant (13/89/12). The views expressed in this publication are those of the authors and not necessarily those of the National Health Service (NHS), the NIHR or the UK Department of Health.

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Contributions of authors

Lauren Young and William McGuire 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.

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Declarations of interest

None known.

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Differences between protocol and review

None noted.

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Characteristics of studies

Characteristics of included studies

Abdelmaaboud 2012

Methods

Randomised controlled trial

Participants

Preterm infants, 28-36 weeks' gestation with birth weight < 10th centile, antenatal ultrasound showing intrauterine growth restriction, absent or reversed end diastolic flow on Doppler waveforms of the umbilical artery with evidence of cerebral redistribution, arterial cord pH ≥ 7.0 and base deficit ≥ -12 and 5-minute Apgar score of > 5.

Infants were excluded if there was any major congenital abnormality, twin-twin transfusion, intrauterine transfusion, exchange transfusion, rhesus iso-immunisation, significant multi-organ failure, inotropic drug support or minimal enteral feeding had already started

Setting: single centre: Women's Hospital, Hamad Medical Corporation, Qatar

Interventions

Early introduction of progressive enteral feeds on day 3 (62 infants) versus late introduction of enteral feeds on day 6 (63 infants)

Outcomes

Incidence of NEC (stage II/III), time to reach full enteral feeds (sustained for 72 hours), rates of feed intolerance, mortality and duration of hospital stay

Notes

> 90% of participants were VLBW

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated tables

Allocation concealment (selection bias) Unclear risk

Not stated

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers not blinded to intervention group

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

No information on blinding of radiological assessors to intervention groups

Incomplete outcome data (attrition bias) Low risk

Complete follow-up assessment

Armanian 2013

Methods

Randomised controlled trial

Participants

VLBW infants

Infants were excluded if there was a congenital abnormality

Setting: Isfahan Faculty of Medicine, Iran

Interventions

Delayed introduction of progressive enteral feeds (only minimal volumes until day 7 (47 infants) versus early introduction on day 3 (35 infants)

Infants received either unfortified breast milk or formula (no subgroup data available). Volumes and rates of advancement or progressive feeds were the same in both groups (20 mL/kg/day)

Outcomes

Incidence of NEC, mortality, days to full enteral feeds, duration of hospital stay

Notes  
Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not stated

Allocation concealment (selection bias) Unclear risk

Not stated

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers not blinded to intervention group

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

No information on blinding of radiological assessors to intervention groups

Incomplete outcome data (attrition bias) Low risk

Complete follow-up assessment

Arnon 2013

Methods

Randomised controlled trial

Participants

Preterm infants, birth weight < 10th centile*, and antenatal evidence of absent or reversed end diastolic flow on Doppler waveforms of the umbilical artery

Infants were excluded if there was a major congenital abnormality, receipt of mechanical ventilation or enteral feeding had already started

Setting: single centre: Meir Medical Centre, Kfar Saba, Tel Aviv, Israel

Interventions

Delayed progressive enteral feeding (day 4-5 after birth, 30 infants) versus earlier enteral feeding (day 2 after birth, 30 infants)

Infants received expressed breast or formula or both

Outcomes

Incidence of NEC, mortality, nosocomial infection, days to reach full enteral feeds, duration of hospital stay

Notes

*Most participants were VLBW (range 963-1683 g)

Original study published in Portuguese

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not stated

Allocation concealment (selection bias) Unclear risk

Not stated

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers not blinded to intervention group

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

No information on blinding of radiological assessors to intervention groups

Incomplete outcome data (attrition bias) Low risk

Complete follow-up assessment

Davey 1994

Methods

Randomised controlled trial

Participants

62 preterm infants with birth weight < 2000 g who were clinically stable and who had an umbilical artery catheter in place

Infants were excluded if they had a lethal condition or had received a double-volume exchange transfusion

Setting: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, US

Interventions

Delayed introduction of enteral feeds (median 5 days; 31 infants) versus earlier introduction (median 2 days; 31 infants)

Infants received either breast milk or diluted formula (no subgroup data available). Volumes and rates of advancement were the same in both groups

Outcomes

Days to regain birth weight, days to full enteral feeding, duration of hospital stay, incidence of NEC and mortality

Notes

The trial inclusion criterion for birth weight was < 2000 g. Since > 80% of infants were VLBW or very preterm, we decided to include the trial

Infants in the delayed introduction group commenced enteral feeds when the umbilical artery catheter had been removed for 24 hours and the infant was clinically stable. Infants in the earlier introduction group commenced feeds with the umbilical artery catheter in situ

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Sequence generation method not reported

Allocation concealment (selection bias) Low risk

Sealed opaque envelopes

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Not stated but unlikely that carers were blinded to intervention groups

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

Not described

Incomplete outcome data (attrition bias) Low risk

The trial excluded 2 infants in the early introduction group post-randomisation due to protocol violation. All other participants were accounted for

Karagianni 2010

Methods

Randomised controlled trial

Participants

84 singleton newborn infants of gestational age 27- 34 weeks' and birth weight < 10th percentile who also had antenatal Doppler ultrasound evidence within 7 days before birth of 'pathological fetal perfusion', defined as uterine or umbilical arterial pulsatility index > 90th percentile and middle cerebral arterial pulsatility index < 10th percentile for gestational age

Infants were excluded with a major congenital anomaly or infection or had received exchange transfusion or inotrope support

Setting: Neonatology Department, Aristotle University, Thessaloniki, Greece

Interventions

Delayed (> 5 days after birth; 42 infants) versus early (≤ 5 days; 42 infants) introduction of enteral feeds (expressed breast milk or preterm formula milk)

Minimal enteral feeding was continued until day 7 after birth and then feed volumes were advanced at daily targeted increments of 15 mL/kg

Outcomes

Incidence of NEC, mortality*, days to full enteral feeds*, duration of hospital stay*

Notes

*Unpublished data courtesy of Dr Karagianni

Of the 84 infants enrolled, 81 completed the study. 3 infants died before 5 days after birth. We have included these infants in the intention-to-treat analysis of mortality > 90% of infants were VLBW

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated sequence

Allocation concealment (selection bias) Low risk

Opaque sealed envelopes

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers and clinical assessors not blinded to allocation groups

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

No information available about blinding of radiological assessors

Incomplete outcome data (attrition bias) Low risk

All data were included in the analyses

Khayata 1987

Methods

Randomised controlled trial

Participants

12 VLBW infants

Interventions

Delayed introduction of enteral feeds (day 10 after birth; 7 infants) versus earlier introduction (< 4 days; 5 infants)

All infants received standard calorie formula. Volumes and rates of advancement were the same in both groups

Outcomes

Growth during the first 6 weeks after birth

Notes

This trial was reported as an abstract only. Further (unpublished) methodological or outcome data were not available

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not described

Allocation concealment (selection bias) Unclear risk

Not described

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Not described but unlikely to be blinded

Blinding (performance bias and detection bias)
Radiological assessments
Unclear risk

Not described

Incomplete outcome data (attrition bias) Unclear risk

Not described

Leaf 2012

Methods

Randomised controlled trial

Participants

404 preterm infants < 35 weeks' gestation and birth weight < 10th percentile and antenatal Doppler ultrasound evidence of:

  1. absent or reversed end diastolic flow velocities on at least 50% of the Doppler waveforms from the umbilical artery on at least 1 occasion during pregnancy


    or

  2. 'cerebral redistribution', defined as occurring when both the umbilical artery pulsatility index > 95th percentile and the middle cerebral artery pulsatility index < 5th percentile for gestational age (Hershkovitz 2000)


    Infants were excluded with a major congenital anomaly, receipt of in-utero transfusion, multi-organ failure or need for inotrope support


    Setting: 54 neonatal care centres in UK and Ireland

Interventions

Delayed (day 5 after birth; 202 infants) versus early (day 2 after birth; 202 infants) introduction of milk feeds

Protocol for advancing feed volumes was the same in both groups

Outcomes

Days to full feeds (150 mL/kg/day) sustained for 3 days, incidence of NEC (all stages, and stage II/III), mortality, invasive infection, time to regain birth weight, duration of hospital stay

Notes

> 90% of infants were VLBW

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Computer-generated sequence

Allocation concealment (selection bias) Low risk

Central telephone randomisation

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers were not blinded to the allocation groups

Blinding (performance bias and detection bias)
Radiological assessments
Low risk

All cases of NEC were reviewed independently by a committee that were blinded to the study groups

Incomplete outcome data (attrition bias) Unclear risk

2 infants (1 from each group) were excluded from the trial after randomisation occurred (error in recruitment and consent withdrawal)

Ostertag 1986

Methods

Randomised controlled trial

Participants

38 VLBW infants assessed to be at 'high risk' of developing NEC based on a risk assessment score

Setting: Perinatology Center, New York Hospital-Cornell Medical Center, New York, USA

Interventions

Delayed introduction of enteral feeds (day 7 after birth; 20 infants) versus earlier introduction (day 1; 18 infants)

Infants received feeds by continuous intragastric infusion starting initially with sterile water, then progressing to 2.5% dextrose, diluted formula, then full-strength standard calorie formula milk. Volumes and rates of advancement were the same in both groups: constant infusion at 1 mL/hour for 7 days then daily increments of 10 mL/kg/day

Outcomes

Incidence of NEC and mortality

Notes

Further details about exclusions after randomisation kindly provided by Dr La Gamma (March 2009)

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Low risk

Random number table

Allocation concealment (selection bias) Unclear risk

Not described

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers not blinded to allocation groups

Blinding (performance bias and detection bias)
Radiological assessments
Low risk

Radiologists reviewing abdominal films were blinded to the group assignments

Incomplete outcome data (attrition bias) Low risk

3 infants died before 7 days after birth. The investigators excluded 1 infant before day 14 because of a feeding protocol violation. We have included all of these infants in the relevant intention-to-treat analyses

Pérez 2011

Methods

Randomised controlled trial

Participants

239 very preterm or VLBW infants. Included infants had not received any previous enteral feeds

Infants were excluded with congenital anomalies of the gastrointestinal tract, intrauterine growth restriction and respiratory or haemodynamic instability

Setting: Ramón González Valencia de Bucaramanga University Hospital, Columbia

Interventions

Delayed enteral feeding (day 5 after birth, 104 infants) versus earlier enteral feeding (day 1-2 after birth, 135 infants)

All infants received a combination of breast and formula milk. Feed volumes exceeded trophic volumes by the third day of enteral feeding

Outcomes

Incidence of NEC, mortality, duration of hospital stay, growth, days to reach full feeds (150 mL/kg/day)

Notes

Original study published in Spanish

Risk of bias table
Bias Authors' judgement Support for judgement
Random sequence generation (selection bias) Unclear risk

Not described (states "randomly assigned", and "controlled clinical trial")

Allocation concealment (selection bias) Low risk

Not described

Blinding (performance bias and detection bias)
Clinical assessments
High risk

Carers or investigators not blinded to allocation groups

Blinding (performance bias and detection bias)
Radiological assessments
Low risk

Abdominal radiographs interpreted by radiologist who was independent from the study and blind to the allocation groups

Incomplete outcome data (attrition bias) Low risk

Complete follow-up assessment for primary outcomes

Footnotes

NEC: necrotising enterocolitis; VLBW: very low birth weight.

Characteristics of excluded studies

Chetry 2014

Reason for exclusion

Both groups received early enteral feeds

Glass 1984

Reason for exclusion

Infants were allocated alternately to either early (first day after birth) or delayed transpyloric enteral feeding. The delayed feeding group commenced enteral nutrition when assessed to be "clinically stable" but this included initiation within 4 days after birth

Higgs 1974

Reason for exclusion

Infants in the delayed progressive enteral feeds group received total parenteral nutrition as a co-intervention

LaGamma 1985

Reason for exclusion

This was not a randomised controlled trial

Said 2008

Reason for exclusion

Infants in the delayed progressive enteral feeding group received minimal enteral nutrition prior to feed advancement as a co-intervention

Sanghvi 2013

Reason for exclusion

Both groups received early enteral feeds

Weiler 2006

Reason for exclusion

Infants in both groups received some enteral feeds before 4 days after birth

Wilson 1997

Reason for exclusion

Infants in the delayed progressive enteral feeds group also received delayed advancement of parenteral nutrition as a co-intervention

Characteristics of studies awaiting classification

None noted.

Characteristics of ongoing studies

None noted.

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References to studies

Included studies

Abdelmaaboud 2012

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(2):1-8.

Armanian 2013

Published and unpublished data

Armanian AM, Mirbod SM, Kazemipour S, Hassanzade A. Comparison of prolonged low volume milk and routine volume milk on incidence of necrotizing enterocolitis in very low birth weight neonates. Pakistan Journal of Medical Sciences 2013;29(1 Suppl):312-6.

Arnon 2013

Arnon S, Sulam D, Konikoff F, Regev RH, Litmanovitz I, Naftali T. Very early feeding in stable small for gestational age preterm infants: a randomized clinical trial. Jornal de Pediatria 2013;89(4):388-93.

Davey 1994

Published data only (unpublished sought but not used)

Davey AM, Wagner CL, Cox C, Kendig JW. Feeding premature infants while low umbilical artery catheters are in place: a prospective, randomized trial. Journal of Pediatrics 1994;124(5 Pt 1):795-9. [PubMed: 8176571]

Karagianni 2010

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(5):367-73. [DOI: 10.1055/s-0029-1243310; PubMed: 20013579]

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

Kempley S, Gupta N, Linsell L, Dorling J, McCormick K, Mannix P. Feeding infants below 29 weeks' gestation with abnormal antenatal Doppler: analysis from a randomised trial. Archives of Disease in Childhood. Fetal and Neonatal Edition 2014;99(1):F6-11. [PubMed: 23973795]

Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Brocklehurst P. ADEPT - Abnormal Doppler Enteral Prescription Trial. BMC Pediatrics 2009;9:63. [DOI: 10.1186/1471-2431-9-63; PubMed: 19799788]

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). In: E-PAS20101670.7. 2010.

* 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(5):1-9. [DOI: 10.1542/peds.2011-2379; PubMed: 22492770]

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. [DOI: 10.1136/adc.2010.192310.4.1]

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(3):275-80. [PubMed: 3081868]

Pérez 2011

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(4):485-91. [DOI: 10.1590/S0120-41572011000400003; PubMed: 22674359]

Excluded studies

Chetry 2014

Chetry S, Kler N, Saluja S, Garg P, Soni A, Thakur A, et al. A randomised control trial comparing initiation of total enteral feeds on 1st day of life with standard feeding regimen in stable very low birth weight infants born between > 30-34 weeks gestation and 1000-1500 gms. In: Pediatric Academic Societies [2930.442]. 2014.

Glass 1984

Glass EJ, Hume R, Lang MA, Forfar JO. Parenteral nutrition compared with transpyloric feeding. Archives of Disease in Childhood 1984;59(2):131-5. [PubMed: 6422864]

Higgs 1974

Higgs SC, Malan AF, De Heese HV. A comparison of oral feeding and total parenteral nutrition in infants of very low birthweight. South African Medical Journal 1974;48(52):2169-73. [PubMed: 4215158]

LaGamma 1985

LaGamma EF, Ostertag S, Birenbaum H. Failure of delayed oral feedings to prevent necrotizing enterocolitis. Results of study in very-low-birth-weight neonates. American Journal of Diseases of Children 1985;139(4):385-9. [PubMed: 3919570]

Said 2008

Said H, Elmetwally D, Said N. Randomized controlled trial of early versus late enteral feeding in prematurely born infants with birth weight ≤ 1200 grams. Kasr El Aini Medical Journal 2008;14:1-10.

Sanghvi 2013

Sanghvi KP, Joshi P, Nabi F, Kabra N. Feasibility of exclusive enteral feeds from birth in VLBW infants >1200 g - an RCT. Acta Paediatrica 2013;102(7):e299-304. [DOI: 10.1111/apa.12254; PubMed: 23621289]

Weiler 2006

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 < or = 1200g improves bone mass by term age. American Journal of Clinical Nutrition 2006;83(1):155-62. [PubMed: 16403735]

Wilson 1997

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. Fetal and Neonatal Edition 1997;77(1):F4-11. [PubMed: 9279175]

Studies awaiting classification

None noted.

Ongoing studies

None noted.

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Other references

Additional references

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(1 Pt 1):198-206. [PubMed: 10649179]

Berrington 2012

Berrington JE, Hearn RI, Bythell M, Wright C, Embleton ND. Deaths in preterm infants: changing pathology over 2 decades. Journal of Pediatrics 2012;160(1):49-53. [DOI: 10.1016/j.jpeds.2011.06.046; PubMed: 21868028]

Berseth 1990

Berseth CL. Neonatal small intestinal motility: motor responses to feeding in term and preterm infants. Journal of Pediatrics 1990;117(5):777-82. [PubMed: 2121949]

Bisquera 2002

Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing enterocolitis on length of stay and hospital charges in very low birth weight infants. Pediatrics 2002;109(3):423-8. [PubMed: 11875136]

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(22):2452-4. [PubMed: 101680]

Burrin 2002

Burrin DG, Stoll B. Key nutrients and growth factors for the neonatal gastrointestinal tract. Clinics in Perinatology 2002;29(1):65-96. [PubMed: 11917740]

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(6):F509-13. [PubMed: 15499143]

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(5):F359-63. [PubMed: 16113150]

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(4):F289-92. [PubMed: 15210657]

Flidel-Rimon 2006

Flidel-Rimon O, Branski D, Shinwell ES. The fear of necrotizing enterocolitis versus achieving optimal growth in preterm infants - an opinion. Acta Paediatrica 2006;95(11):1341-4. [PubMed: 17062457]

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(2):481-7. [PubMed: 15343225]

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(4):464-70. [DOI: 10.1097/MPG.0b013e31818c5fc3; PubMed: 19322056]

Hay 2008

Hay WW Jr. Strategies for feeding the preterm infant. Neonatology 2008;94(4):245-54. [DOI: 10.1159/000151643; PubMed: 18836284]

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(2):F120-3. [PubMed: 17768154]

Hershkovitz 2000

Hershkovitz R, Kingdom JC, Geary M, Rodeck CH. Fetal cerebral blood flow redistribution in late gestation: identification of compromise in small fetuses with normal umbilical artery Doppler. Ultrasound in Obstetrics & Gynecology 2000;15(3):209-12. [PubMed: 10846776]

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, 2011. Available from www.cochrane-handbook.org.

Holman 2006

Holman RC, Stoll BJ, Curns AT, Yorita KL, Steiner CA, Schonberger LB. Necrotising enterocolitis hospitalisations among neonates in the United States. Paediatric and Perinatal Epidemiology 2006;20(6):498-506. [PubMed: 17052286]

Kamoji 2008

Kamoji VM, Dorling JS, Manktelow B, Draper ES, Field DJ. Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants. Acta Paediatrica 2008;97(3):327-31. [Other: 10.1111/j.1651-2227.2008.00671.x; PubMed: 18298781]

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(1):F56-61. [DOI: 10.1136/adc.2010.204123; PubMed: 21856644]

Morgan 2013a

Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD000504. DOI: 10.1002/14651858.CD000504.pub3.

Narayanan 1981

Narayanan I, Prakash K, Gujral VV. The value of human milk in the prevention of infection in the high-risk low-birth-weight infant. Journal of Pediatrics 1981;99(3):496-8. [PubMed: 6790690]

Patole 2004

Patole S, Muller R. Enteral feeding of preterm neonates: a survey of Australian neonatologists. Journal of Maternal-Fetal & Neonatal Medicine 2004;16(5):309-14. [PubMed: 15621549]

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(2):F147-51. [PubMed: 15724039]

Premji 2011

Premji SS, Chessell L. Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD001819. DOI: 10.1002/14651858.CD001819.pub2.

Quigley 2014

Quigley MA, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD002971. DOI: 10.1002/14651858.CD002971.pub2.

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(3):F193-8. [PubMed: 16984980]

RevMan 2011

Review Manager (RevMan) [Computer program]. Version 5.1. Copenhagen: Nordic Cochrane Centre. The Cochrane Collaboration, 2011.

Roberts 2006

Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD004454. DOI: 10.1002/14651858.CD004454.pub2.

Seger 2009

Seger N, Soll R. Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD007836. DOI: 10.1002/14651858.CD007836.

Soll 2009

Soll R, Ozek E. Multiple versus single doses of exogenous surfactant for the prevention or treatment of neonatal respiratory distress syndrome. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD000141. DOI: 10.1002/14651858.CD000141.pub2.

Soll 2010

Soll R, Ozek E. Prophylactic protein free synthetic surfactant for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2010, Issue 1. Art. No.: CD001079. DOI: 10.1002/14651858.CD001079.pub2.

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(19):2357-65. [PubMed: 15547163]

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Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas initiating enteral feedings in high risk infants: how can they be resolved? Seminars in Perinatology 2007;31(2):61-73. [PubMed: 17462490]

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Other published versions of this review

Bombell 2008

Bombell S, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub2.

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. Art. No.: CD001970. 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. Art. No.: CD001970. DOI: 10.1002/14651858.CD001970.pub3.

Morgan 2013b

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.

Classification pending references

None noted.

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Data and analyses

1 Delayed versus early introduction of progressive enteral feeding

For graphical representations of the data/results in this table, please use link under "Outcome or Subgroup."

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Necrotising enterocolitis 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.1.1 All trials 8 1092 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.64, 1.34]
  1.1.2 Trials of infants with intrauterine growth restriction or abnormal antenatal Doppler flow velocities 4 673 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.54, 1.41]
1.2 Mortality prior to discharge 7 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.2.1 All trials 7 967 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.75, 1.88]
  1.2.2 Trials of infants with intrauterine growth restriction or abnormal antenatal Doppler flow velocities 3 548 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.55, 2.05]
1.3 Feed intolerance 3 288 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.62, 1.15]
1.4 Incidence of invasive infection 2 457 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.95, 1.70]
1.5 Duration of hospital admission (days) 3 346 Mean Difference (IV, Fixed, 95% CI) 2.11 [0.31, 3.90]
 

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Figures

Figure 1

Refer to figure 1 caption below.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 1 description).

Figure 2 (Analysis 1.1)

Refer to figure 2 caption below.

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

Figure 3 (Analysis 1.2)

Refer to figure 3 caption below.

Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.2 Mortality prior to discharge (Figure 3 description).

Figure 4 (Analysis 1.3)

Refer to figure 4 caption below.

Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.3 Feed intolerance (Figure 4 description).

Figure 5 (Analysis 1.5)

Refer to figure 5 caption below.

Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.5 Duration of hospital admission (days) (Figure 5 description).

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Sources of support

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 was 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

This review is published as a Cochrane review in The Cochrane Library, Issue 12, 2014 (see http://www.thecochranelibrary.com External Web Site Policy for information).  Cochrane reviews are regularly updated as new evidence emerges and in response to feedback.  The Cochrane Library should be consulted for the most recent version of the review.