Home > Health & Research > Health Education Campaigns & Programs > Cochrane Neonatal Review > Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants

Skip sharing on social media links
Share this:

Authors

Jessie Morgan1, Lauren Young2, 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]
2Paediatric Intensive Care Unit, Birmingham Children's Hospital, Birmingham, UK [top]

Citation example: Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2015, Issue 10. Art. No.: CD001241. DOI: 10.1002/14651858.CD001241.pub6.

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: 10 September 2015
Date of Search: 03 September 2015
Next Stage Expected: 03 September 2017
Protocol First Published: Issue 4, 1998
Review First Published: Issue 4, 1998
Last Citation Issue: Issue 10, 2015

[top]

What's new

Date / Event Description
31 July 2015
New citation: conclusions changed

The updated search identified three new trials for inclusion (Raban 2014a; Raban 2014b; Modi 2015). This increased the total number of participating infants to 949 (from 618). This update provides evidence that slow advancement of enteral feed volumes increases the risk of invasive infection in very low birth weight infants.

31 July 2015
Updated

This updates the review 'Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants' (Morgan 2014b).

[top]

History

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

Addition of new data, and increasing the total number of participating infants to 496, narrowed the confidence intervals for the estimates of effect and modified the implications for practice and research.

15 December 2010
Updated

This updates the review "Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 2, 2008 (McGuire 2008).

Search updated in December 2010. One new trial included (Krishnamurthy 2010).

New co-authors: Jessie Morgan and Lauren Young.

13 February 2008
New citation: conclusions not changed

New authorship: Bombell S, McGuire W

02 February 2008
Updated

This updates the review "Rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants" by Kennedy and Tyson, published in the Cochrane Database of Systematic Reviews, Issue 2, 2000 (Kennedy 2000).

The title has been modified to read "Slow advancement of enteral feed volumes 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. "Slow" rate of feed advancement has been defined as daily increments up to 24 ml/kg (body weight).
2. The population has been restricted to very low birth weight and very preterm infants.
3. Mortality, adverse neurodevelopment, growth parameters, and infection rates have been included as outcomes of interest.

Search updated December 2007. One new trial has been included (Salhotra 2004). One trial previously included has now been excluded (Book 1976).

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

11 January 2008
Amended

Converted to new review format.

[top]

Abstract

Background

Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis (NEC) in very preterm or very low birth weight (VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes, reduce the risk of NEC. However, slow feed advancement may delay establishment of full enteral feeding and be associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition.

Objectives

To determine the effect of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review group to search the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 7), MEDLINE via PubMed (1966 to August 2015), EMBASE (1980 to August 2015), and CINAHL (1982 to August 2015). We also searched clinical trials databases, conference proceedings, previous reviews, and the reference lists of retrieved articles for randomised controlled trials and quasi-randomised trials.

Selection criteria

Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 mL/kg/day) versus faster rates of advancement of enteral feed volumes upon the incidence of NEC 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 (RD) 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 949 infants participated. Most participants were stable preterm infants with birth weights between 1000 and 1500 g. Fewer participants were extremely preterm, extremely low birth weight, or growth-restricted. The trials typically defined slow advancement as daily increments of 15 to 24 mL/kg and faster advancement as 30 to 40 mL/kg. Meta-analyses did not show statistically significant effects on the risk of NEC (typical RR 1.02, 95% CI 0.64 to 1.62; typical RD -0.00, 95% CI -0.03 to 0.03) or all-cause mortality (typical RR 1.18, 95% CI 0.90 to 1.53; typical RD 0.03, 95% CI -0.02 to 0.08). Slow feeds advancement delayed the establishment of full enteral nutrition by one to five days and increased the risk of invasive infection (typical RR 1.46, 95% CI 1.03 to 2.06; typical RD 0.07, 95% CI 0.01 to 0.13; number needed to treat for an additional harmful outcome 14, 95% CI 8 to 100).

Authors' conclusions

The available trial data suggest that advancing enteral feed volumes at daily increments of 30 to 40 mL/kg (compared to 15 to 24 mL/kg) does not increase the risk of NEC or death in VLBW infants. Advancing the volume of enteral feeds at slow rates results in several days of delay in establishing full enteral feeds and increases the risk of invasive infection. The applicability of these findings to extremely preterm, extremely low birth weight, or growth-restricted infants is limited. Further randomised controlled trials in these populations may be warranted to resolve this uncertainty.

[top]

Plain language summary

Slowly advancing milk feeds does not reduce the risk of necrotising enterocolitis in very low birth weight infants

 

Review question

Does limiting the rate of increase in the amount of milk feeds that very low birth weight infants receive each day for the first few weeks after birth reduce the risk of severe bowel problems?

Background

Very low birth weight infants (infants less than 1500 g at birth) are at risk of developing a severe bowel disorder called necrotising enterocolitis, where the bowel becomes inflamed and dies). It is thought that one possible way to prevent this condition is to limit the amount of milk feeds that infants receive each day for the first few weeks after birth.

Study characteristics

We searched scientific databases for clinical trials comparing slow versus faster rates of feeds advancement in newborn infants who were preterm (less than 32' gestation (time spent within the mother's body)) or very low birth weight. We found nine trials involving 949 infants.

Key results

Combined analysis of these trials did not show an effect of slow feeding on the risk of necrotising enterocolitis but did suggest that infants fed more slowly had a higher risk of acquiring a severe infection than infants fed more quickly.

Conclusions

Slow feeding does not appear to have any benefits and may cause some serious harms.

[top]

Background

Description of the condition

Necrotising enterocolitis (NEC), a syndrome of acute intestinal necrosis of unknown aetiology, affects about 5% of very preterm (less than 32 weeks) or very low birth weight (VLBW) (less than 1500 g) infants (Holman 1997). Infants who develop NEC experience more nosocomial infections, have lower levels of nutrient intake, grow more slowly, and have longer durations of intensive care and hospital stay than gestation-comparable infants who do not develop NEC (Bisquera 2002; Guthrie 2003). The associated mortality rate is more than 20%. Compared with their peers, infants who develop NEC have a higher incidence of long-term neurological disability, which may be a consequence of infection and under-nutrition during a critical period of brain development (Stoll 2004; Soraisham 2006; Rees 2007; Pike 2012).

Description of the intervention

Short gestational age at birth is the major clinical risk factor for developing NEC (Beeby 1992; Luig 2005). The other putative major risk factor is intrauterine growth restriction, especially if associated with absent or reversed end-diastolic flow velocities in Doppler studies of the fetal aorta or umbilical artery (Bernstein 2000; Garite 2004; Dorling 2005). 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). Other differences in enteral feeding regimens, such as the timing of introduction of feeds and the size of the daily volume increments, may also contribute to inter-unit variation in the incidence of NEC. Multicentre benchmarking studies have found that those neonatal centres where enteral feeding is introduced earlier and feeding volumes advanced more quickly tend to have higher incidences of NEC (Uauy 1991). Observational studies have suggested that delaying the introduction of enteral feeds beyond the first few days after birth, or increasing the volume of feeds by less than about 20 to 24 mL/kg body weight each day, is associated with a lower risk of developing NEC in very preterm or VLBW infants (Brown 1978; McKeown 1992; Patole 2005; Henderson 2009).

Why it is important to do this review

Potential disadvantages associated with slowing the advancement of enteral feed volumes include delaying the establishment of full enteral nutrition and extending the duration of receipt of parenteral nutrition (Flidel-Rimon 2004). Prolonged use of parenteral nutrition is associated with infectious and metabolic risks that may have adverse consequences for survival, growth, and development (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; Chauhan 2008; Härtel 2009).

Other Cochrane reviews have addressed the questions of whether delaying the introduction of any enteral milk feeding or restricting feed volumes to trophic levels (minimal enteral nutrition) affect the risk of NEC in very preterm or VLBW infants (Morgan 2013; Morgan 2014a). This review focused on the question of whether advancing feed volumes at slow rates compared to faster rates affected the risk of NEC, mortality, and other morbidities.

[top]

Objectives

To determine the effect of slow rates of enteral feed advancement on the incidence of NEC, mortality, and other morbidities in very preterm or VLBW infants.

[top]

Methods

Criteria for considering studies for this review

Types of studies

Controlled trials utilising either random or quasi-random participant allocation.

Types of participants

Enterally fed very preterm (less than 32 weeks) or VLBW (less than 1500 g) newborn infants.

Types of interventions

Advancement of enteral feeds at no more than 24 mL/kg (birth weight or current body weight) per day versus faster rates of feeds advancement. Infants should have received the same type of milk and in both groups, the advancement of feed volume should have commenced within five days of introduction of enteral feeds.

Types of outcome measures

Primary outcomes
  • 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 a combination of these);
  • or a diagnosis confirmed at surgery or autopsy (Walsh 1986).
  • All-cause mortality during the neonatal period and prior to hospital discharge.
Secondary outcomes
  • Growth.
    • 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).
    • Long-term growth: weight, height, or head circumference (or proportion of infants who remained below the 10th percentile for the index population's distribution) assessed at intervals from six months of age.
  • Neurodevelopment
    • Death or severe neurodevelopmental disability defined as any one or a combination of the following: non-ambulatory cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component was to be analysed individually as well as part of the composite outcome.
    • Neurodevelopmental scores in survivors aged 12 months or greater measured using validated assessment tools.
    • Cognitive and educational outcomes in survivors aged more than five years.
  • Time to establish full enteral feeding (independently of parenteral nutrition).
  • Time to establish oral feeding (independently of parenteral nutrition or enteral tube feeding, or both).
  • Feed intolerance (defined as a requirement to cease enteral feeds).
  • Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine, or from a normally sterile body space.
  • Duration of hospital stay (days).

Search methods for identification of studies

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

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 7), MEDLINE (1966 to August 2015), EMBASE (1980 to August 2015), and CINAHL (1982 to August 2015) 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. We did not apply any language restrictions.

We searched ClinicalTrials.gov External Web Site Policy for completed or ongoing trials.

Searching other resources

We examined the reference lists of all studies identified as potentially relevant.

We searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2015), the European Society for Paediatric Research (1995 to 2014), the UK Royal College of Paediatrics and Child Health (2000 to 2015), and the Perinatal Society of Australia and New Zealand (2000 to 2015). 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 (Cochrane Neonatal Review Group External Web Site Policy).

Selection of studies

Two review authors screened the titles and abstracts of all studies identified by the above search strategy. We assessed the full texts 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 achieved 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 Cochrane and the Cochrane Neonatal Group to assess the methodological quality of all included trials (Higgins 2011). 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.

Sequence generation (the method used to generate the allocation sequence):

  • low risk: any truly random process (e.g. random number table, computer random number generator);
  • high risk: any non-random process (e.g. odd or even date of birth, hospital or clinic record number);
  • unclear risk: no or unclear information provided.

Allocation concealment (the method used to conceal the allocation sequence):

  • low risk (e.g. telephone or central randomisation; consecutively numbered, sealed, opaque envelopes);
  • high risk: open random allocation (e.g. unsealed or non-opaque envelopes, alternation, date of birth);
  • unclear: no or unclear information provided.

Blinding (the methods used to ensure blinding of participants, clinicians, and carers, and outcome assessors):

  • low risk;
  • high risk;
  • unclear.

Incomplete outcome data (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 reinstated missing data in the analyses. We categorised completeness as:

  • low risk: adequate (less than 10% missing data);
  • high risk: inadequate (greater than 10% missing data);
  • unclear risk: no or unclear information provided.

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). When we deemed it appropriate to combine two or more study arms, we obtained the treatment effects from the combined data using the methods described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We determined the number needed to treat for an additional beneficial outcome (NNTB) or harmful outcome (NNTH) for a statistically significant difference in the RD.

Unit of analysis issues

The unit of analysis was the participating infant in individually randomised trials and the neonatal unit (or subunit) 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 the heterogeneity between trial results by inspecting the forest plots. We calculated the I2 statistic for each analysis to quantify inconsistency across studies and to describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If we detected substantial heterogeneity (I2 greater than 50%), 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 2014).

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses:

  • trials in which most infants were exclusively formula fed;
  • trials in which most infants were at least partially fed with human milk (maternal or donor);
  • trials in which most participants were of extremely low birth weight (ELBW) (less than 1000 g) or extremely preterm gestational age (less than 28 weeks);
  • trials in which participants were infants with intrauterine growth restriction or infants with absent or reversed end-diastolic flow velocities detected on antenatal Doppler studies of the fetal aorta or umbilical artery.

[top]

Main results

Description of studies

Nine randomised controlled trials fulfilled the review eligibility criteria (Rayyis 1999; Caple 2004; Salhotra 2004; Krishnamurthy 2010; Karagol 2013; Mukhopadhyay 2014; Raban 2014a; Raban 2014b; Modi 2015) (see Characteristics of included studies table).

Included studies

Population

A total of 949 infants participated in the included trials. The trials were undertaken in neonatal care centres in North America (Rayyis 1999; Caple 2004), India (Salhotra 2004; Krishnamurthy 2010; Mukhopadhyay 2014; Modi 2015), Turkey (Karagol 2013), and South Africa (Raban 2014a; Raban 2014b).

All of the trials specified participant birth weight eligibility criteria:

Since most participants in Caple 2004 were of birth weight less than 1500 g or gestational age less than 32 weeks, we made a consensus decision to include the trial. Infants born 'small for gestational age' (birth weight less than 10th percentile of the index population's distribution) were not eligible to participate in Caple 2004 but were included in the other trials. More than 95% of the participants in Salhotra 2004 were 'small for gestational age'. One-third of participants in Karagol 2013 were ELBW infants. All participants in Mukhopadhyay 2014 had antenatal evidence of absent or reversed end-diastolic flow.

Interventions and comparisons

All trials commenced interval bolus intragastric feeding within one to five days after birth. Infants were randomly allocated to one of two rates of daily increments in enteral feed volume:

In one trial, only formula-fed infants were eligible to participate (Rayyis 1999). In Caple 2004, Krishnamurthy 2010, Karagol 2013, Mukhopadhyay 2014, and Modi 2015, infants received either expressed breast milk or formula, or a combination of the two. In Salhotra 2004, Raban 2014a, and Raban 2014b, participating infants were fed exclusively with expressed breast milk. All of the trial protocols specified indications for interrupting or ceasing enteral feeding, such as residual gastric contents of more than about one-third of the previous feed volume, frequent vomiting, abdominal distention, or detection of blood in the stools (including occult blood).

Outcomes

All of the trials reported the incidence of NEC confirmed radiologically or at surgery or autopsy. The other reported outcomes included time to regain birth weight, time to establish full enteral feeding, duration of hospital stay, and rates of invasive infection.

Excluded studies

We excluded Book 1976 and Berseth 2003 (see Characteristics of excluded studies). In Book 1976, enteral feeding volumes were advanced at 10 mL/kg/day versus 20 mL/kg/day, that is both groups received 'slow' advancement of feed volumes. In Berseth 2003, infants were randomly allocated to either a stable (not progressively increased) trophic feeding volume or to feed volume advancement at 20 mL/kg/day.

Risk of bias in included studies

The methodological quality of the included trials was generally good. All trials employed methods to ensure adequate allocation concealment and reported complete or near-complete assessments of the primary outcomes. None of the trials were able to conceal the feeding strategies from parents, carers, or clinical investigators. Three studies clearly masked the assessment of abdominal radiographs (for diagnosis of NEC). In Salhotra 2004, Karagol 2013, Raban 2014a, Raban 2014b, and Modi 2015, it was unclear whether precautions had been taken to ensure that radiological assessors were blinded to the allocation group.

Effects of interventions

Primary outcomes

Incidence of necrotising enterocolitis (Outcome 1.1)

Meta-analysis did not detect a statistically significant effect on the risk of NEC (typical RR 1.02, 95% CI 0.64 to 1.62; typical RD -0.00, 95% CI -0.03 to 0.03; 9 studies, 949 infants; I2 = 26%) (Analysis 1.1; Figure 1).

Mortality (Outcome 1.2)

Meta-analysis did not detect a statistically significant effect on the risk of mortality (typical RR 1.18, 95% CI 0.90 to 1.53; typical RD 0.03, 95% CI -0.02 to 0.08; 8 studies, 791 infants; I2 = 17%) (Analysis 1.2; Figure 2).

Secondary outcomes

Growth

Seven trials reported that infants in the slow-rate-of-advancement group took a statistically significantly longer time to regain birth weight:

Mukhopadhyay 2014 and Modi 2015 did not report growth.

None of the trials reported longer-term growth parameters.

Neurodevelopment

None of the trials assessed neurodevelopmental outcomes.

Time to establish full enteral feeding

Seven of the trials reported that it took statistically significantly longer to establish full enteral feeds in infants in the slow-rate-of-advancement group:

Raban 2014a and Raban 2014b did not report this outcome.

Time to establish full oral feeding

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

Feeds intolerance (causing interruption of enteral feeding) (Outcome 1.3)

Meta-analysis of data from seven trials (606 infants) found no statistically significant difference in feeds intolerance (typical RR 1.20, 95% CI 0.95 to 1.50; typical RD 0.06, 95% CI -0.01 to 0.13; I2 = 0%) (Analysis 1.3; Figure 3).

Incidence of invasive infection (Outcome 1.4)

Meta-analysis of data from six trials (553 infants) showed a statistically significant higher risk in infants who received slow advancement of enteral feed volumes (typical RR 1.46, 95% CI 1.03 to 2.06; typical RD 0.07, 95% CI 0.01 to 0.13; NNTH 14, 95% CI 8 to 100; I2 = 0%) (Analysis 1.4; Figure 4).

Duration of hospital stay

Four trials did not detect a statistically significant difference in duration of hospital stay:

Two trials reported that the duration of hospital stay was statistically significantly longer in infants in the slow-rate-of-advancement group:

The other trials did not report duration of hospital stay (Salhotra 2004; Mukhopadhyay 2014; Modi 2015).

Subgroup analyses

  • Exclusively formula-fed infants (Rayyis 1999). No statistically significant differences:
    • NEC: RR 1.44 (95% CI 0.63 to 3.32); RD 0.04 (95% CI -0.05 to 0.13);
    • mortality: RR 0.59 (95% CI 0.10 to 3.46); RD -0.01 (95% CI -0.06 to 0.03).
  • Infants at least partially fed with human milk. Subgroup data not available.
  • Extremely preterm or ELBW infants (Raban 2014a; Raban 2014b). No statistically significant differences:
    • NEC: typical RR 1.05 (95% CI 0.44 to 2.51); typical RD 0.00 (95% CI -0.08 to 0.08); 2 studies, 200 infants; I2 = 87% (Figure 1);
    • mortality: typical RR 0.83 (95% CI 0.55 to 1.25); typical RD -0.06 (95% CI -0.19 to 0.07); 2 studies, 200 infants; I2 = 41% (Figure 2).
  • Infants with intrauterine growth restriction or absent or reversed end-diastolic flow velocities (Salhotra 2004; Mukhopadhyay 2014). No statistically significant difference in NEC, but borderline significant increase in mortality in slow advancement group:
    • NEC: typical RR 0.34 (95% CI 0.06 to 2.04); typical RD -0.07 (95% CI -0.18 to 0.04); 2 studies, 83 infants; I2 = 0% (Figure 1);
    • mortality: typical RR 2.13 (95% CI 1.02 to 4.47); typical RD 0.02 (95% CI 0.02 to 0.38); NNTH 5 (95% CI 3 to 50); 2 studies, 83 infants; I2 = 0% (Figure 2).

[top]

Discussion

Summary of main results

The available trial data showed that advancing enteral feed volumes at slow rates (typically 15 to 24 mL/kg/day) compared to faster rates (30 to 40 mL/kg/day) did not affect the risk of NEC in VLBW infants. The boundaries of the 95% CI for the estimate of effect were narrow; consistent with either three extra or three fewer cases of NEC in every 100 infants who have slow rates of feed advancement. Meta-analysis of data from these trials did not show a statistically significant effect on all-cause mortality but a pre-specified subgroup analysis showed a statistically significant increase in risk of death with slow advancement in infants with growth restriction or antenatal absent end-diastolic flow velocities. However, this finding is based on data from only two small trials with 83 participants and should be interpreted cautiously. Meta-analysis of data from six trials showed a higher risk of late-onset infection in infants who had slow advancement of enteral feeds. The point estimate suggested that an extra episode of late-onset infection occurs for every 14 infants who have slow feed advancement.

Infants who had slow advancement of feed volumes regained their birth weight several days later than infants who had faster rates of advancement of feed volumes but the clinical importance of this effect was unclear. Longer-term growth or developmental outcomes were not assessed. Similarly, infants who had slow advancement of feed volumes established full enteral feeding one to five days later than infants who had faster rates of advancement of feed volumes. Despite this, the included trials did not show consistent evidence of an important effect on the duration of hospital admission.

Overall completeness and applicability of evidence

These findings should be applied with caution for several reasons. Most of the trial participants were preterm infants with birth weight between 1000 and 1500 g. Only two trials specifically recruited ELBW infants, and very few participants were of birth weight less than 750 g (Raban 2014a; Raban 2014b). One-third of the infants in Karagol 2013 were of ELBW, but only a smaller minority of infants in the other trials were ELBW or had evidence of intrauterine growth restriction. Infants who had severe respiratory distress requiring oxygen supplementation or ventilatory support were not eligible to participate in three of the trials (Salhotra 2004; Krishnamurthy 2010; Karagol 2013). Therefore, the review findings may not be applicable to these populations at highest risk of developing feed intolerance or NEC (Luig 2005).

More than half of all of the participating infants were fed with breast milk. Evidence exists that artificial-formula feeding increases the risk of feed intolerance and 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. It is also unclear whether the findings can be applied to infants who receive continuous infusion of intragastric feeds, as all of the infants in the included trials received enteral feeds as interval boluses. Randomised controlled trials have reported conflicting findings about the effect of continuous enteral infusion on feed tolerance in very preterm or VLBW infants (Premji 2011).

Although the finding that slow enteral feed volume advancement delays the establishment of full enteral feeds may seem intuitive, it is also plausible that advancing feed volumes faster could have resulted in more feed intolerance and therefore a delay in the establishment of full enteral feeding. The included trials pre-specified definitions of feed intolerance that mandated interrupting or ceasing feed volume advancement, principally the detection of 'gastric residuals' (the gastric content aspirated prior to a planned gastric tube feed) and abdominal distension. However, the trial reports presented only limited data on the frequency of these outcomes. Furthermore, there is only limited evidence that the volume or colour of gastric residuals is predictive of the risk of NEC for infants whose feed volumes are advanced conservatively (Mihatsch 2002; Cobb 2004; Bertino 2009). Similarly, the clinical importance of abdominal distension or bowel loops visible through the abdominal wall (without other features of intra-abdominal pathology) is unclear, especially in the modern era, when early and prolonged use of continuous positive airway pressure results in intestinal gaseous distension.

Quality of the evidence

The included trials were generally of good methodological quality but, in common with other trials of feeding interventions in this population, it was not possible to mask carers and clinical assessors to the nature of the intervention (Figure 5). Although the lack of blinding may have resulted in surveillance and ascertainment biases, it is more likely to have caused an overestimation of the incidence of feed intolerance and NEC in infants whose feed volumes were advanced faster. The assessment of abdominal radiographs for signs of NEC was masked in most trials to ensure that the diagnosis of severe 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 over-ascertainment of NEC in the infants who had faster rates of feed volume advancement (Tyson 2007).

Agreements and disagreements with other studies or reviews

This review focused specifically on the comparison of slow versus faster rates of feed volume advancement and did not compare progressive advancement with enteral fasting or trophic feeding (minimal enteral nutrition). Only one randomised controlled trial has compared trophic feeding with progressive enteral feed volume advancement (at daily increments of 20 mL/kg) (Berseth 2003). Although the trial found the risk of NEC to be statistically significantly higher in the infants whose feed volumes were progressively advanced, this finding should be interpreted cautiously. The trial was stopped early following an interim analysis, therefore the finding of an effect on the incidence of NEC may be spurious (Montori 2005). Carers and assessors were not blind to the intervention. As discussed above, this may have resulted in several sources of bias that are likely to cause an overestimation of the incidence of NEC in infants whose feed volumes are being advanced.

[top]

Authors' conclusions

Implications for practice

These data suggest that advancing enteral feed volumes at daily increments of up to 30 to 40 mL/kg does not increase the risk of feed intolerance, necrotising enterocolitis (NEC), or death in very low birth weight (VLBW) infants. Increasing the volume of enteral feeds at slow rates (less than 24 mL/kg/day) resulted in several days of delay in the time taken to regain birth weight and establish full enteral feeds, and increased the risk of late-onset invasive infection. Only limited data were available on the effect of this intervention on outcomes for extremely preterm or extremely low birth weight (ELBW) infants or infants who were growth-restricted. Although current practice tends to favour a conservative approach to enteral feeding in these populations, clinicians should consider that there are other possible consequences of advancing feed volumes slowly, such as prolonging the use of parenteral nutrition, which may be associated with important adverse clinical outcomes.

Implications for research

Further randomised controlled trials could provide more precise estimates of the effects of different rates of daily increases in enteral feed volumes on important outcomes for extremely preterm or ELBW infants. Trials should aim to ensure the participation of infants with evidence of compromised intrauterine growth, so that subgroup analyses can be planned for this population at high risk of NEC. Masking carers and investigators to the nature of this intervention is probably not 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 such 'competing outcomes' as invasive infection that may affect long-term survival and neurodisability rates, it is essential that trials are powered and structured to assess these outcomes.

[top]

Acknowledgements

We are grateful to Drs Namasivayam Ambalavanan, Kanya Mukhopadhyay, and Manoj Modi for providing further details and data (Rayyis 1999; Mukhopadhyay 2014; Modi 2015).

[top]

Contributions of authors

Drs Morgan, Young, and 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.

[top]

Declarations of interest

WM is a member of the SIFT Investigators' Group. SIFT (Speed of Increasing milk Feeds Trial) is a large, pragmatic randomised controlled trial of slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (SIFT 2013).

[top]

Characteristics of studies

Characteristics of included studies

Caple 2004

Methods

Randomised controlled trial

Participants

Preterm infants of birth weight 1000-2000 g (appropriate birth weight for gestational age and of gestational age < 35 weeks at birth), who were starting formula feeds

Setting: Neonatal Unit, Department of Pediatrics, University of Texas Medical School, Houston, Texas, USA

Interventions

Feeds advancement at 20 mL/kg/day (n = 74) versus 30 mL/kg/day (n = 84)

Outcomes

NEC (Bell stage II/III)
Time to regain birth weight, time to achieve full enteral feeds, and time to hospital discharge

Notes

Feeds were ceased if the residual gastric aspirate was more than one-third of the previous feed volume, or if there was frequent vomiting, abdominal distention, or bloody stools (including occult blood)

We were unable to obtain data on all-cause mortality from the principal investigators

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

Random number sequence

Allocation concealment (selection bias) Low risk

Blinded draw from envelope by carers not involved in study

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

Carers and clinical investigators were not blinded once allocation to intervention groups had occurred

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

Radiologists interpreting X-rays were blinded to the intervention group

Incomplete outcome data (attrition bias) Low risk

3 infants excluded after enrolment because of protocol violations were included in this review and meta-analysis. 2 infants (1 in each group) were excluded because they were determined not eligible for enrolment because of an in utero gastrointestinal perforation and fetal alcohol syndrome; these infants were not included in the meta-analysis

Karagol 2013

Methods

Randomised controlled trial

Participants

Preterm infants < 32 weeks' gestation with birth weights of 750-1250 g. 32% of infants weighed < 1000 g

Exclusion criteria included major congenital malformations, severe respiratory distress, presence of umbilical vessel catheters, contraindications to enteral feeding, perinatal asphyxia, or cardiovascular compromise

Setting: Division of Neonatology, Dr Sami Ulus Maternity, Children's Education and Research Hospital, Ankara, Turkey

Interventions

Slow advancement at 20 mL/kg/day (n = 46) versus rapid advancement at 30 mL/kg/day (n = 46)

Outcomes

NEC (stage II/III), all-cause mortality, time to regain birth weight, time to reach full enteral feeds, feed intolerance, duration of hospital stay, rates of invasive infection

Subgroup analysis for ELBW infants

Notes

Feeds were ceased if any of the following occurred: gastric residuals > 5 mL/kg or > 50% of feed volume, vomiting > 3 times in 24 hours, increase in abdominal girth > 2 cm between feeds, abdominal tenderness or erythema, reduced bowel sounds, blood in the stools, or recurrent apnoea

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 study investigators were not blinded

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

No reference to whether staff interpreting radiological images were blinded to the study groups

Incomplete outcome data (attrition bias) Low risk

No participants lost to follow-up

Krishnamurthy 2010

Methods

Randomised controlled trial

Participants

Preterm infants (birth weight 1000-1499 g) and gestational age < 34 weeks at birth

Exclusion criteria included respiratory distress, mechanical ventilation, inotrope support, and umbilical arterial or venous catheterisation

Setting: Department of Paediatrics, University College of Medical Sciences, Delhi, India

Interventions

Feeds advancement at 20 mL/kg/day (n = 50) versus 30 mL/kg/day (n = 50)

Outcomes

NEC (stage II/III)

Incidence of nosocomial infection, in-hospital mortality, time to regain birth weight, time to achieve full enteral feeds, and time to hospital discharge

Notes

All feeds were delivered by gavage via nasogastric tubes at 2-hour intervals

Feeds were ceased if any of the following occurred: residual gastric contents > 50% of the previous feed volume (delayed if volume was 25-50%), > 3 episodes of apnoea in the preceding hour, abdominal distention or tenderness, or bloody stools (including occult blood)

Parenteral nutrition was not available

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 investigators were not blinded to the interventions

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

Radiologist interpreting X-rays was blinded to the intervention group

Incomplete outcome data (attrition bias) Low risk

No loss to follow-up

Modi 2015

Methods

Randomised controlled trial

Participants

Newborn infants with birth weights of 750-1250 g who commence enteral feeds within 4 days after birth. Mean gestational age of participants was 31 weeks

Exclusion criteria were "gross congenital malformation and anomalies of gastrointestinal tract (intestinal atresia, imperforated anus etc)"

Setting: Department of Neonatology, Maulana Azad Medical College, New Delhi, India

Interventions

Feeds advancement at 15-20 mL/kg/day (n = 65) versus 30-40 mL/kg/day (n = 66)

Outcomes

NEC (stage II/III)

Incidence of feed intolerance, nosocomial infection, in-hospital (all cause) mortality, mean daily weight gain, time to achieve full enteral feeds

Notes

Published as abstract only

Further information from: www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=5289 External Web Site Policy

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

Stratified block randomisation

Allocation concealment (selection bias) Low risk

Sequentially numbered, sealed, opaque envelopes

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

Unblinded

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

Not described

Incomplete outcome data (attrition bias) Low risk

No loss to follow-up

Mukhopadhyay 2014

Methods

Randomised controlled trial

Participants

Preterm infants (birth weight 1000-1249 g) and gestational age > 30 weeks at birth who have antenatal evidence of absent end diastolic flow velocities (presumed in umbilical artery)

Setting: Department of Paediatrics, Postgraduate Institute of Medical Education & Research, Chandigarh, India

Interventions

Feeds advancement at 20 mL/kg/day (n = 15) versus 30 mL/kg/day (n = 15)

Outcomes

NEC (all stages)

Late-onset bloodstream (culture-positive) infection, in-hospital mortality, time to achieve full enteral feeds

Notes

Pre-specified subgroup of larger trial that enrolled infants with birth weight > 1250 g and compared feed advancement at 30 mL/kg/day versus 40 mL/kg/day

Published as conference abstract; further data courtesy of Dr Mukhopadhyay (September 2014)

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

Computer-generated

Allocation concealment (selection bias) Low risk

Sealed, opaque envelopes

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

Carers and investigators were not blinded to the interventions

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

Not stated

Incomplete outcome data (attrition bias) Low risk

Complete follow-up for primary outcomes

Raban 2014a

Methods

Randomised controlled trial (2 × 2 factorial design with Raban 2014b)

Participants

Infants with birth weight less than/or equal to 1000 g

Setting: Groote Schuur Hospital in Cape Town, South Africa (2011-2013)

Interventions

Feeds advancement (from 12 mL/kg/day on day 2) in daily increments of 24 mL/kg (n = 51) versus 36 mL/kg (n = 47) until enteral feeds of 200 mL/kg/day were attained

Outcomes

Time to attain 1500 g of weight, time to regain birth weight, mortality, feed intolerance, NEC, invasive infection

Notes

Factorial design also randomised to commending feeds on day 1 (24 mL/kg) or day 2 (12 mL/kg)

Infants received either maternal expressed breast milk or donor breast milk

Trial registration: ISRCTN96923718

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

Computer-generated

Allocation concealment (selection bias) Unclear risk

Not described

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

Carers and investigators were not blinded to the interventions

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

Not stated

Incomplete outcome data (attrition bias) Low risk

Complete follow-up for primary outcomes

Raban 2014b

Methods

Randomised controlled trial (2 × 2 factorial design with Raban 2014a)

Participants

Infants with birth weight less than/or equal to 1000 g

Setting: Groote Schuur Hospital in Cape Town, South Africa (2011-2013)

Interventions

Feeds advancement (from 24 mL/kg/day on day 1) in daily increments of 24 mL/kg (n = 52) versus 36 mL/kg (n = 50) until enteral feeds of 200 mL/kg/day were attained

Outcomes

Time to attain 1500 g of weight, time to regain birth weight, mortality, feed intolerance, NEC, invasive infection

Notes

Factorial design also randomised to commending feeds on day 1 (24 mL/kg) or day 2 (12 mL/kg)

Infants received either maternal expressed breast milk or donor breast milk

Trial registration: ISRCTN96923718

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

Computer-generated

Allocation concealment (selection bias) Unclear risk

Not described

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

Carers and investigators were not blinded to the interventions

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

Not stated

Incomplete outcome data (attrition bias) Low risk

Complete follow-up for primary outcomes

Rayyis 1999

Methods

Randomised controlled trial

Participants

Very low birth weight infants of gestational age < 34 weeks at birth

Setting: Neonatal Unit, Department of Pediatrics, University of Alabama, Birmingham, Alabama, USA

Interventions

Feeds advancement at 15 mL/kg/day (n = 98) versus 35 mL/kg/day (n = 87)

Outcomes

NEC (stage II/III), time to regain birth weight, time to achieve full enteral feeds, and time to hospital discharge

Notes

Infants for whom full or partial feeding with expressed breast milk was planned were not eligible to participate. Feeding was commenced using standard 'term' artificial formula, then switched to nutrient-enriched 'preterm' formula when full enteral feeding had been achieved. Feeds were ceased if any of the following occurred: residual gastric contents > 30% of the previous feed volume, abdominal distention or tenderness, or bloody stools (including occult blood)

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

Not stated

Allocation concealment (selection bias) Low risk

Opaque, sealed envelopes

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

Carers and investigators not blinded to the intervention groups

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

Radiologist interpreting the X-rays was blinded to the study group

Incomplete outcome data (attrition bias) Low risk

7 protocol violations occurred after enrolment, but all infants were included the final data analysis

Salhotra 2004

Methods

Randomised controlled trial

Participants

Preterm infants of birth weight < 1250 g. > 95% of the participants were 'small for gestational age'

Exclusion criteria included recurrent apnoea, respiratory distress requiring supplemental oxygen, and receipt of inotrope support

Setting: Neonatal Unit, Maulana Azad Medical College (tertiary-level teaching hospital), New Delhi, India

Interventions

Feeds advancement at 15 mL/kg/day (n = 26) versus 30 mL/kg/day (n = 27)

Outcomes

NEC (stage II/III), neonatal mortality, time to regain birth weight, time to achieve full enteral feeds, and time to hospital discharge

Notes

Feeds were ceased if the residual gastric content was > 30% of the previous feed volume or if there was abdominal distention

Mortality data courtesy of Dr Namasivayam Ambalavanan

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

Investigators were blinded at allocation stage, but it is unclear if they remained blinded thereafter. Carers were not blinded to intervention group

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

No statement about blinding of radiological assessors to intervention group

Incomplete outcome data (attrition bias) Low risk

No losses to follow-up

Footnotes

ELBW: extremely low birth weight; n: number of infants; NEC: necrotising enterocolitis.

Characteristics of excluded studies

Berseth 2003

Reason for exclusion

Infants were randomly allocated to either a stable (not progressively increased) trophic feeding volume or to feed volume advancement at 20 mL/kg/day

Book 1976

Reason for exclusion

Enteral feeding volumes were advanced at 10 mL/kg/day versus 20 mL/kg/day, that is both groups received 'slow' advancement of feed volumes

Characteristics of ongoing studies

SIFT 2013

Study name

Speed of Infant Feeding Trial (SIFT)

Methods

Randomised controlled trial

Participants

Very preterm or very low birth weight infants

Interventions

Slow (18 mL/kg/day) versus faster (30 mL/kg/day) advancement of enteral feed volumes

Outcomes

Death or neurodisability by 18-24 months post term

Starting date

2013

Contact information

www.npeu.ox.ac.uk/sift External Web Site Policy

Notes

Recruitment completed June 2015

[top]

References to studies

Included studies

Caple 2004

Caple J, Armentrout D, Huseby V, Halbardier B, Garcia J, Sparks JW, et al. Randomized, controlled trial of slow versus rapid feeding volume advancement in preterm infants. Pediatrics 2004;114(6):1597-600. [PubMed: 15574620]

Karagol 2013

Karagol BS, Zenciroglu A, Okumus N, Polin RA. Randomized controlled trial of slow versus rapid enteral feeding advancements on the clinical outcomes of preterm infants with 750-1250g. Journal of Parenteral and Enteral Nutrition 2013;37(2):223-8. [PubMed: 22664861]

Krishnamurthy 2010

Krishnamurthy S, Gupta P, Debnath S, Gomber S. Slow versus rapid enteral feeding advancement in preterm newborn infants 1000-1499 g: a randomized controlled trial. Acta Paediatrica 2010;99(1):42-6. [PubMed: 20002013]

Modi 2015

Modi M, Ranji S, Jain A, Sharma P, Gupta N. A randomised trial of aggressive feeding regimen in infants with birth weight less than/or equal to 1250 grams. In: Proceedings of the Pediatric Academic Societies Annual Conference; 2015 Apr 25-28; San Diego, CA. 2015.

Mukhopadhyay 2014

Mukhopadhyay K, Jain S. Feed intolerance and necrotising enterocolitis in rapid vs slow feeding in preterm neonates with absent end diastolic flow: a randomised controlled trial. In: Proceedings of the Pediatric Academic Societies and Asian Society for Pediatric Research; 2014 May 3-6; Vancouver. 2014.

Raban 2014a

Raban MS, Santhakumaran S, Keraan Q, Joolay Y, Uthaya S, Horn AR, et al. A randomised controlled trial of high or low volume initiation and rapid or slow advancement of milk feeds for infants less than/or equal to 1000 g. In: Proceedings of the South African Paediatric Association Congress; 2014 Sept 10-14; Cape Town. 2014. [DOI: 10.1186/ISRCTN96923718]

Raban 2014b

Raban MS, Santhakumaran S, Keraan Q, Joolay Y, Uthaya S, Horn AR, et al. A randomised controlled trial of high or low volume initiation and rapid or slow advancement of milk feeds for infants less than/or equal to 1000 g. In: Proceedings of the South African Paediatric Association Congress; 2014 Sept 10-14; Cape Town. 2014. [DOI: 10.1186/ISRCTN96923718]

Rayyis 1999

Rayyis SF, Ambalavanan N, Wright L, Carlo WA. Randomized trial of "slow" versus "fast" feed advancements on the incidence of necrotizing enterocolitis in very low birth weight infants. Journal of Pediatrics 1999;134(3):293-7. [PubMed: 10064664]

Salhotra 2004

Salhotra A, Ramji S. Slow versus fast enteral feed advancement in very low birth weight infants: a randomized control trial. Indian Pediatrics 2004;41(5):435-41. [PubMed: 15181294]

Excluded studies

Berseth 2003

Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding volumes early in life decreases the incidence of necrotizing enterocolitis in very low birth weight infants. Pediatrics 2003;111(3):529-34. [PubMed: 12612232]

Book 1976

Book LS, Herbst JJ, Jung AL. Comparison of fast- and slow-feeding rate schedules to the development of necrotizing enterocolitis. Journal of Pediatrics 1976;89(3):462-6. [PubMed: 989057]

Studies awaiting classification

None noted.

Ongoing studies

SIFT 2013

SIFT Investigators Group. Early enteral feeding strategies for very preterm infants: current evidence from Cochrane reviews. Archives of Disease in Childhood. Fetal and Neonatal Edition 2013;98(6):F470-2. [PubMed: 23766343]

[top]

Other references

Additional references

Beeby 1992

Beeby PJ, Jeffery H. Risk factors for necrotising enterocolitis: the influence of gestational age. Archives of Disease in Childhood 1992;67(4 Spec No):423-5. [PubMed: 1586186]

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]

Bertino 2009

Bertino E, Giuliani F, Prandi G, Coscia A, Martano C, Fabris C. Necrotizing enterocolitis: risk factor analysis and role of gastric residuals in very low birth weight infants. Journal of Pediatric Gastroenterology and Nutrition 2009;48(4):437-42. [PubMed: 19330932]

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]

Brown 1978

Brown EG, Sweet AY. Preventing necrotizing enterocolitis in neonates. JAMA 1978;240(22):2452-4.

Chauhan 2008

Chauhan M, Henderson G, McGuire W. Enteral feeding for very low birth weight infants: reducing the risk of necrotising enterocolitis. Archives of Disease in Childhood. Fetal and Neonatal Edition 2008;93(2):F162-6. [PubMed: 18006565]

Cobb 2004

Cobb BA, Carlo WA, Ambalavanan N. Gastric residuals and their relationship to necrotizing enterocolitis in very low birth weight infants. Pediatrics 2004;113(1 Pt 1):50-3. [PubMed: 14702446]

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]

Guthrie 2003

Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J, Clark RH. Necrotizing enterocolitis among neonates in the United States. Journal of Perinatology 2003;23(4):278-85. [PubMed: 12774133]

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]

Higgins 2011

Higgins JPT, Green S (editors). 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 1997

Holman RC, Stoll BJ, Clarke MJ, Glass RI. The epidemiology of necrotizing enterocolitis infant mortality in the United States. American Journal of Public Health 1997;87(12):2026-31. [PubMed: 9431297]

Härtel 2009

Härtel 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. [PubMed: 19322056]

Luig 2005

Luig M, Lui K; NSW & ACT NICUS Group. Epidemiology of necrotizing enterocolitis - part II: risks and susceptibility of premature infants during the surfactant era: a regional study. Journal of Paediatrics and Child Health 2005;41(4):174-9. [PubMed: 15813870]

McKeown 1992

McKeown RE, Marsh TD, Amarnath U, Garrison CZ, Addy CL, Thompson SJ, et al. Role of delayed feeding and of feeding increments in necrotizing enterocolitis. Journal of Pediatrics 1992;121(5 Pt 1):764-70. [PubMed: 1432431]

Mihatsch 2002

Mihatsch WA, von Schoenaich P, Fahnenstich H, Dehne N, Ebbecke H, Plath C, et al. The significance of gastric residuals in the early enteral feeding advancement of extremely low birth weight infants. Pediatrics 2002;109(3):457-9. [PubMed: 11875141]

Montori 2005

Montori VM, Devereaux PJ, Adhikari NK, Burns KE, Eggert CH, Briel M, et al. Randomized trials stopped early for benefit: a systematic review. JAMA 2005;294(17):2203-9. [PubMed: 16264162]

Morgan 2013

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. [PubMed: 19588318]

Morgan 2014a

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.pub3. [PubMed: 21412877]

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]

Pike 2012

Pike K, Brocklehurst P, Jones D, Kenyon S, Salt A, Taylor D, et al. Outcomes at 7 years for babies who developed neonatal necrotising enterocolitis: the ORACLE Children Study. Archives of Disease in Childhood. Fetal and Neonatal Edition 2012;97(5):F318-22. [PubMed: 22933088]

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. [PubMed: 22071802]

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. [PubMed: 24752468]

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 2014

Review Manager (RevMan) [Computer program]. Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Soraisham 2006

Soraisham AS, Amin HJ, Al-Hindi MY, Singhal N, Sauve RS. Does necrotising enterocolitis impact the neurodevelopmental and growth outcomes in preterm infants with birthweight < or =1250 g? Journal of Paediatrics and Child Health 2006;42(9):499-504. [PubMed: 16925534]

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]

Tyson 2007

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]

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(4):630-8. [PubMed: 1919897]

Walsh 1986

Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment based on staging criteria. Pediatric Clinics of North America 1986;33(1):179-201. [PubMed: 3081865]

Other published versions of this review

Kennedy 2005

Kennedy KA, Tyson JE, Chamnanvanakij S. Rapid versus slow rate of advancement of feedings for promoting growth and preventing necrotizing enterocolitis in parenterally fed low-birth-weight infants. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD001241. DOI: 10.1002/14651858.CD001241.pub2.

McGuire 2008

McGuire W, Bombell S. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD001241. DOI: 10.1002/14651858.CD001241.pub2. [PubMed: 18425870]

Morgan 2011

Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD001241. DOI: 10.1002/14651858.CD001241.pub3. [PubMed: 21412870]

Morgan 2014b

Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD001241. DOI: 10.1002/14651858.CD001241.pub4. [PubMed: 23543511]

[top]

Data and analyses

1 Slow versus faster rates of feed advancement

Outcome or Subgroup Studies Participants Statistical Method Effect Estimate
1.1 Incidence of necrotising enterocolitis 9 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.1.1 All trials 9 949 Risk Ratio (M-H, Fixed, 95% CI) 1.02 [0.64, 1.62]
  1.1.2 Trials in which most infants were extremely preterm or extremely low birth weight 2 200 Risk Ratio (M-H, Fixed, 95% CI) 1.05 [0.44, 2.51]
  1.1.3 Trials in which most infants were small for gestational age or growth restricted 2 83 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.06, 2.04]
1.2 Mortality 8 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
  1.2.1 All trials 8 791 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.90, 1.53]
  1.2.2 Trials in which most infants were extremely preterm or extremely low birth weight 2 200 Risk Ratio (M-H, Fixed, 95% CI) 0.83 [0.55, 1.25]
  1.2.3 Trials in which most infants were small for gestational age or growth restricted 2 83 Risk Ratio (M-H, Fixed, 95% CI) 2.13 [1.02, 4.47]
1.3 Feeds intolerance (causing interruption of enteral feeding) 7 606 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [0.95, 1.50]
1.4 Incidence of invasive infection 6 553 Risk Ratio (M-H, Fixed, 95% CI) 1.46 [1.03, 2.06]
 

[top]

Figures

Figure 1 (Analysis 1.1)

Refer to Figure 1 caption below.

Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.1 Incidence of necrotising enterocolitis (Figure 1).

Figure 2 (Analysis 1.2)

Refer to Figure 2 caption below.

Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.2 Mortality (Figure 2).

Figure 3 (Analysis 1.3)

Refer to Figure 3 caption below.

Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.3 Feeds intolerance (causing interruption of enteral feeding) (Figure 3).

Figure 4 (Analysis 1.4)

Refer to Figure 4 caption below.

Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.4 Incidence of invasive infection (Figure 4).

Figure 5

Refer to Figure 5 caption below.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies (Figure 5).

[top]

Sources of support

Internal sources

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

External sources

  • National Institute for Health Research (NIHR), UK

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

  • 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.


This review is published as a Cochrane review in The Cochrane Library, Issue 10, 2015 (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 recent version of the review.