Necrotising enterocolitis is an important cause of morbidity, mortality and long term neurodisability in very low birth weight infants. Extremely low birth weight and extremely preterm infants are at greatest risk (Bisquera 2002; Holman 2006; Rees 2007). Intrauterine growth restriction may be an additional specific risk factor, especially if associated with circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in antenatal Doppler studies of the fetal aorta or umbilical artery (Bernstein 2000; Garite 2004; Dorling 2005).
Most very low birth weight infants who develop necrotising enterocolitis have received enteral milk feeds. Evidence exists that feeding with formula milk increases the risk (Quigley 2007). The timing of the introduction and the rate of progression of enteral feed volumes may be modifiable risk factors for the development of necrotising enterocolitis (Brown 1978; Uauy 1991). Data from observational studies suggest that adopting standardised feeding regimens that include delaying the introduction of progressive enteral feeds for about five to seven days after birth reduces the risk of necrotising enterocolitis (Patole 2005).
In current clinical practice, the introduction of progressive enteral feeds for very low birth weight infants is often preceded by a period of enteral fasting or "trophic feeding" (feed volumes up to 24 ml/kg/day) (Boyle 2004; Patole 2004; Dorling 2005). 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 have adverse consequences for survival, duration of hospital stay, growth and development (Flidel-Rimon 2004; Stoll 2004). It has been argued that the risk of necrotising enterocolitis should not be considered in isolation of these other potential clinical outcomes when determining feeding policies and practice for very low birth weight infants (Flidel-Rimon 2006).
This review focuses on the comparison of delayed versus earlier introduction of progressive enteral feeding; that is, advancing the volume of milk feeds beyond "trophic" levels. The effect of trophic feeding, the early introduction of small volume enteral feeds (up to 24 ml/kg/day) without advancing the feed volumes for at least five days versus enteral fasting is addressed in the Cochrane review "Early trophic feeding for very low birth weight infants" (Bombell 2009).
To determine the effect of delayed introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very low birth weight infants.
The following subgroup analyses were planned:
- Exclusively formula milk-fed infants.
- Infants were fully or partially fed with breast milk (maternal or donor).
- Extremely low birth weight (less than 1000 grams) or extremely preterm (less than 28 weeks' gestation at birth).
- 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.
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials or cluster randomised trials.
Types of participants
Very low birth weight (less than 1500 grams) or very preterm (less than 32 weeks' gestation) newborn infants.
Types of interventions
Delayed introduction of progressive enteral feeds (more than four days after birth) versus earlier introduction of enteral feeds. Progressive enteral feeding was defined as feed volumes in excess of trophic feeds (24 ml/kg/day or 1 ml/kg/hour). Infants should have received the same type of milk (breast milk or formula), the same route and mode of feeding (intragastric or transpyloric, bolus gavage or continuous) and the same rate of feed volume advancement in both groups.
Types of outcome measures
1. Necrotising enterocolitis confirmed by at least two of the following features:
- abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen
- abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both)
- blood in stool
- lethargy, hypotonia, or apnoea (or combination of these);
or a diagnosis confirmed at surgery or autopsy (Walsh 1986).
2. All-cause mortality during the neonatal period and prior to hospital discharge.
3. Growth: (i) Time to regain birth weight and subsequent rates of weight gain, linear growth, head growth, or skinfold thickness growth up to 6 months' age corrected for preterm birth.
(ii) Long-term growth: weight, height, or head circumference and/or proportion of infants who remain below the tenth percentile for the index population's distribution assessed at intervals from six months of age.
4. Neurodevelopment: (i) Death or severe neurodevelopmental disability defined as any one or combination of the following: non-ambulatory cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component will be analysed individually as well as part of the composite outcome.
(ii) Neurodevelopmental scores in survivors aged greater than or equal to 12 months' of age measured using validated assessment tools.
(iii) Cognitive and educational outcomes in survivors aged more than five years old.
5. Time to establish full enteral feeding (days)
6. Time to establish oral feeding independently of parenteral nutrition and/or enteral tube feeding (days)
7. Episodes of feed intolerance resulting in an interruption or cessation of progression of enteral feeds
8. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal-spinal fluid, urine or from a normally sterile body space
9. Duration of hospital stay (days)
Search methods for identification of studies
The standard search strategy of the Cochrane Neonatal Group was used. Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2009), MEDLINE (1966 - February 2009), EMBASE (1980 - February 2009), and CINAHL (1982 - February 2009) [via OVID] using the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR infan* OR neonat*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula OR trophic feeding OR minimal enteral nutrition OR gut priming ]. The search outputs were limited with the relevant search filters for clinical trials. No language restriction was applied.
References in previous reviews and studies were examined. The abstracts presented at the Society for Pediatric Research and European Society for Pediatric Research between 1990 and 2008 were searched. 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. The UK National Research Register (http://www.nrr.nhs.uk), and Current Controlled Trials (http://www.controlled-trials.com) websites was searched for completed or ongoing trials.
Data collection and analysis
1. The title and abstract of all studies identified by the above search strategy were screened and the full articles for all potentially relevant trials obtained. The full text of any potentially eligible reports was reassessed and those studies that did not meet all of the inclusion criteria were excluded. Any disagreements were discussed until consensus was achieved.
2. The criteria and standard methods of the Cochrane Neonatal Review Group were used to independently assess the methodological quality of any included trials in terms of allocation concealment, blinding of parents or caregivers and assessors to the intervention, and completeness of assessment in all randomised individuals. Additional information from the trial authors was requested to clarify methodology and results as necessary.
3. A data collection form was used to aid extraction of relevant information from each included study. Each review author extracted the data separately. Any disagreements were discussed until consensus was achieved. If data from the trial reports were insufficient, the trialists were contacted for further information.
4. Meta-analyses were performed using the fixed effects model. Relative risk and risk difference were calculated for dichotomous data and weighted mean difference for continuous data, with respective 95% confidence intervals (CI). The number needed to treat and associated 95% CI were determined for a statistically significant reduction in the risk difference. The treatment effects of individual trials and heterogeneity between trial results was examined by inspecting the forest plots. The impact of heterogeneity in any meta-analysis was assessed using the I- squared statistic. If statistical heterogeneity was noted, the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) were explored using post-hoc subgroup analyses.
Description of studies
Three small trials fulfilled the review eligibility criteria (Davey 1994; Ostertag 1986; Khayata 1987; see table 'Characteristics of Included Studies'). Four studies were excluded (Glass 1984; Higgs 1974; LaGamma 1985; Wilson 1997; see table 'Characteristics of Excluded Studies').
Davey 1994: Clinically stable preterm infants of birth weight less than 2000 grams who had a low umbilical artery catheter in situ (N = 62) were randomly allocated to either initiation of progressive enteral feeding before the catheter was removed (median two days after birth) or delayed introduction of feeding 24 hours after the catheter was removed (median five days after birth). Participating infants were fed with formula milk or breast milk (subgroup data no available). The concentration and volume of enteral feeds were increased at the same rates in both groups. Reported outcomes included days to regain birth weight, days to achieve full enteral feeding, duration of hospital stay, discharge weight, feed intolerance, necrotising enterocolitis, and mortality.
Khayata 1987: Very low birth weight infants (N = 12) were randomised to either an early progressive feeding group (started within 96 hours after birth) or a late feeding group started at 10 days or later using the same schedule as the early feeding group. The trial was reported in abstract form and only limited information on methodology and outcomes is available.
Ostertag 1986 Very low birth weight infants assessed with a risk score to be at high risk of developing necrotising enterocolitis (N = 41) were randomised to early (day one) or delayed (day seven) enteral feeding. Feeds were delivered as a continuous infusion of 1ml/hour for seven days then in incremental advances of 10 ml/kg/day. Reported outcomes were necrotising enterocolitis, and mortality.
Risk of bias in included studies
Quality assessments are included in the Table, 'Characteristics of Included Studies'.
Davey 1994: Allocation was concealed using sequentially-numbered opaque sealed envelopes. Caregivers and investigators were aware of the allocated feeding regimen but it is likely that the clinicians who assessed abdominal radiographs were blinded to treatment group. Follow-up was nearly complete; two infants in the "early feeding" group were excluded from the trial post-randomisation because of protocol violation (umbilical artery catheter removed before feeding).
Khayata 1987: The method of randomisation was not described. It is likely that caregivers and investigators were not blind to the intervention. Follow-up assessments were likely to have been undertaken on all participants.
Ostertag 1986: The precise method of randomisation was not described. Caregivers and investigators were not blind to the intervention. Follow-up assessments were reported for all participants.
Effects of interventions
DELAYED VS. EARLY INTRODUCTION OF ENTERAL FEEDS (COMPARISON 1)
Necrotising enterocolitis (Outcome 1.1: two trials). Davey 1994 and Ostertag 1986 did not detect a statistically significant effect: typical relative risk 1.27 (95% CI 0.54, 3.00); typical risk difference 0.04 (95% CI -0.10, 0.18).
Mortality (Outcome 1.2: two trials): Davey 1994 and Ostertag 1986 did not detect a statistically significant effect: typical relative risk 0.31 (95% CI 0.01, 7.38); typical risk difference -0.03 (95% CI -0.12, 0.05).
Growth (Outcome 1.3: two trials): Davey 1994 did not detect a statistically significant difference in the median time to regain birth weight (13 days for both groups). Khayata 1987 reported no significant difference in the rate of weight gain during the first six weeks after birth: mean difference -1.00 (95% CI -127.4, 125.4) g/kg/week. Long-term growth parameters were not reported by either of the trials.
Neurodevelopment: Neither trial assessed neurodevelopmental outcomes.
Time to establish full enteral feeding (one trial): Davey 1994 did not find a statistically significant difference in time taken to establish enteral feeding (median 19 versus 22.5 days after birth) but the median duration of use of parenteral nutrition was longer in the delayed (30 days) compared with the early introduction group (13 days).
Time to establish full oral feeding: Not reported by either of the included trials.
Feed intolerance: Davey 1994 found no statistically significant differences in the proportion of infants who had gastric residual volumes more than 20% of the preceding feed volume, abdominal distention (daily increment in abdominal girth of at least 2 cm) or enteral feeding interrupted or ceased because of feed intolerance.
Incidence of invasive infection: Not reported by either trial. Davey 1994 found that significantly more infants in the delayed group underwent "sepsis evaluations" (52% versus 17% in the early group).
Duration of hospital stay (Outcome 01.04: one trial): Davey 1994 did not find a statistically significant difference in the median duration of hospital admission (60 versus 47 days). There was no significant difference in the postmenstrual age at discharge: mean difference 0.90 (95% CI -1.21, 3.01) weeks.
- Exclusively formula milk-fed infants: No subgroup data available.
- Infants were at least partially fed with breast milk: No subgroup data available.
- Extremely low birth weight or extremely preterm: It is likely that less than one-third of all participants were extremely low birth weight or extremely preterm but no subgroup data were available.
- 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: No subgroup data available.
The trials that have assessed the effect of delaying the introduction of progressive enteral feeds in very low birth weight infants do not provide sufficient evidence to guide clinical practice. All were small and were underpowered to exclude important effects on the risk of necrotising enterocolitis, mortality, and other morbidities. None assessed any long-term outcomes. Given this paucity of trial evidence, current practice is largely informed by data from observational studies that have found that delaying the introduction of progressive enteral feeds is associated with a reduced risk of necrotising enterocolitis. However, since delaying the introduction of progressive enteral feeds may also have potential disadvantages related to the prolonged use of parenteral nutrition, this practice may not result in an overall benefit for very low birth weight infants (Flidel-Rimon 2004; Flidel-Rimon 2006).
Further large randomised controlled trials are needed to provide robust evidence to inform this fundamental area of neonatal care. Trials could assess the effects of delayed introduction of progressive enteral feeding preceded either by a period of enteral fasting or trophic feeding. Initial trophic feeding may be preferred given that it is not associated with a statistically significant effect on the risk of necrotising enterocolitis (Bombell 2009). Furthermore, mothers who express breast milk for early trophic feeding are more likely to continue to provide breast milk as the on-going principal form of nutrition for their infants (Schanler 1999). Evidence exists that feeding with breast milk compared to formula reduces the risk of necrotising enterocolitis in very low birth weight infants (Lucas 1990; Quigley 2007).
Undertaking trials of feeding interventions in this population is problematic (Tyson 2007). It is difficult to design a pragmatic trial that will ensure that caregivers and investigators are unaware of the allocated feeding regimen. This lack of blinding may cause surveillance and ascertainment biases that result in over-estimation of the incidence of feed intolerance and necrotising enterocolitis in infants whose feeds are introduced earlier. A priori agreements on objective definitions of feed intolerance and indications for interruption of enteral feeding and for investigation of necrotising enterocolitis may help minimise the impact of this source of bias. Diagnosing "confirmed" necrotising enterocolitis on the basis of radiological detection of gas in the bowel wall or portal tract is also prone to bias because intraluminal milk is a substrate for the microbial generation of intestinal gas. Infants who have received more enteral milk may be more likely to demonstrate radiological signs than infants with equally severe bowel disease who have less intraluminal substrate. Given these problems, and since conservative feeding strategies may result in other competing outcomes such as nosocomial infection secondary to prolonged use of parenteral nutrition, it is essential that trials are powered and structured to assess more objective outcomes, principally long-term disability-free survival rates.
The definition of delayed introduction of progressive feeds may vary between different subpopulations of very low birth weight infants who have different empiric risks for developing feed intolerance and necrotising enterocolitis. For example, the effects of enteral feeding are likely to be very different for a ventilator and/or inotrope dependent infant of birth weight less than 700 grams compared with a clinically-stable infant of birth weight more than 1400 grams. For this Cochrane review, delayed introduction was defined as later than four days after birth since various observational studies have found the risk of necrotising enterocolitis to be lower when feeds are introduced five to seven days after birth (Patole 2005). For extremely low birth weight or extremely preterm infants, it may be more appropriate to define delayed introduction as more than seven days after birth (or even later). Small intestinal motility is poorly organised before about 28 weeks' gestation resulting in a higher risk of feed intolerance. Additionally, enteral feeds are often delayed in this population because of respiratory or metabolic instability or because of other putative risk factors for necrotising enterocolitis such as the existence of a patent ductus arteriosus, the use of non-steroidal anti-inflammatory agents, or the presence of a umbilical arterial catheter.
Infants who are growth restricted because of suboptimal placental support are also considered to at greater risk of developing necrotising enterocolitis (Stoll 2004). Despite the potential for nutritional disadvantage, enteral feeding is often delayed for a week or more after birth in infants who are severely growth restricted, especially if there is evidence of circulatory redistribution or reduced gastrointestinal perfusion (Dorling 2005). Paradoxically, this population of infants has been specifically excluded from participating in many trials of early enteral feeding practices. There are no data on this subgroup for the two small trials included in this review. However, an on-going multicentre trial is currently examining the effect of delayed introduction of progressive enteral feeds on the risk of necrotising enterocolitis and other morbidities in infants with severe growth restriction and evidence of circulatory redistribution (see: www.npeu.ox.ac.uk/adept/). When data from this trial are available they will be included in an update of this review.
Finally, the applicability of trials undertaken in high-income settings to neonatal care in middle- and low-income countries (and vice versa) is unclear. Conservative strategies such as delayed introduction or slow advancement of feed volumes may confer less nutritional disadvantage in settings where adjunctive parenteral nutrition is readily and safely available. In settings with less technologically-developed healthcare provision where parenteral nutrition is not available and where severe infection (diarrhoea, pneumonia, septicaemia) is much more important cause of mortality and morbidity, the nutritional and immunological advantages of early feeding with breast milk may outweigh any risks associated with enteral feeding for very low birth weight infants (Narayanan 1982; de Silva 2004).
Implications for practice
There are insufficient data from randomised controlled trials to determine the effect of delaying the introduction of progressive enteral feeds on the risk of necrotising enterocolitis, mortality, and other morbidities in very low birth weight infants.
Implications for research
Further randomised controlled trials are needed to determine the optimal time to introduce progressive enteral feeds for very low birth weight infants. Future trials should be simple and pragmatic to ensure high levels of acceptance and participation. Trials should aim to ensure the participation of extremely low birth weight and extremely preterm infants as well as infants with evidence of compromised intrauterine growth so that subgroup analyses can be planned for these populations at high risk of necrotising enterocolitis. Masking caregivers and investigators to the nature of this intervention is unlikely to be possible. Since the unblinded evaluation of feed intolerance and necrotising enterocolitis is subject to surveillance and ascertainment biases, trials should 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 that may affect long-term survival and neurodisability rates, it is essential that trials are powered and structured to assess these outcomes.
We gratefully acknowledge the contributions of Drs Kennedy, Tyson, and Chamnanvanakij, the authors of the previous version of this Cochrane review (Kennedy 2000).
We are grateful to Ms Kate Light (Information Specialist, CRD, University of York) for developing and running the updated electronic search.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Index terms
Last assessed as up-to-date: 19 March 2009.
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998
Contributions of authors
William McGuire and Sarah Bombell independently assessed the methodological quality of the included trials, extracted the relevant information and data, and completed the final review.
Declarations of interest
Medical Subject Headings (MeSH)
MeSH check words