Description of the condition
Necrotising enterocolitis is an important cause of morbidity and mortality in very preterm (< 32 weeks) or very low birth weight (VLBW: < 1500 grams) infants. Extremely low birth weight (ELBW: < 1000 grams) and extremely preterm (< 28 weeks) infants are at highest risk (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 (AREDFV) in antenatal Doppler studies of the fetal aorta or umbilical artery (Bernstein 2000; Dorling 2005).
Most very preterm or VLBW infants who develop necrotising enterocolitis have received enteral milk feeds. Evidence exists that feeding with formula milk rather than breast milk increases the risk (Lucas 1990; Quigley 2007; Meinzen-Derr 2009). The timing of the introduction of enteral feeding may also be an important modifiable risk factor for the development of necrotising enterocolitis (Henderson 2009). Observational data suggest that feeding strategies that include delaying the introduction of progressive enteral feeds until after five to seven days postnatally reduces the risk of necrotising enterocolitis in very preterm or VLBW infants (Patole 2005). However, enteral fasting during the early neonatal period also has potential disadvantages. Because gastrointestinal hormone secretion and motility are stimulated by enteral milk, delayed enteral feeding could diminish the functional adaptation of the immature gastrointestinal tract (Johnson 1976; Aynsley-Green 1983; Berseth 1990). Consequent intestinal dysmotility may exacerbate feed intolerance leading to a delay in establishing enteral feeding independently of parenteral nutrition. Enteral fasting might also cause hyperbilirubinaemia by increasing enterohepatic recirculation of bilirubin and delaying hepatic enzyme maturation. 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; Flidel-Rimon 2006).
Description of the intervention
Trophic feeding (also referred to as minimal enteral nutrition, gut priming and hypocaloric feeding) was developed and adopted into clinical practice as an alternative to complete enteral fasting for very preterm or VLBW infants during the early neonatal period (Klingenberg 2012). Early trophic feeding is conventionally defined as giving small volumes of milk (typically 12 to 24 ml/kg/day) intragastrically starting within the first few days after birth, without advancing the feed volumes during the first week postnatally (McClure 2001). The primary aim of trophic feeding is to accelerate gastrointestinal physiological, endocrine and metabolic maturity and so allow infants to transition to full enteral feeding independent of parenteral nutrition more quickly. However, any beneficial effects may be negated if early trophic feeding increases the risk of necrotising enterocolitis in very preterm or VLBW infants.
Why it is important to do this review
This review focuses on the question of whether early trophic feeding compared with a similar period of enteral fasting improves feed tolerance without increasing the risk of necrotising enterocolitis in very preterm or VLBW infants. Other Cochrane reviews address the questions of whether introducing progressive enteral milk feeds (beyond trophic volumes) later or slowing the rate of advancement of feed volumes affects the risk of necrotising enterocolitis, mortality and other morbidities (Morgan 2011a; Morgan 2011b).
To determine the effect of early trophic feeding versus enteral fasting on feed tolerance, growth and development, and the incidence of neonatal morbidity (including necrotising enterocolitis and invasive infection) and mortality in very preterm or VLBW infants.
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials including cluster-randomised trials.
Types of participants
VLBW (< 1500 grams) or very preterm (< 32 weeks) newborn infants.
Types of interventions
Early trophic feeding: enteral feeding with milk volumes up to 24 ml/kg/day (1 ml/kg/hour) beginning within four days after birth and continued for at least five days or until at least one week after birth versus enteral fasting for the same period.
Once progressive enteral feeding has started, 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
- Feed intolerance: days to establish full enteral feeding independently of parenteral nutrition.
- 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).
- All-cause mortality prior to hospital discharge.
- Growth: (i) Time to regain birth weight and rates of weight gain, linear growth, head growth or skinfold thickness growth up to six months of age corrected for preterm birth; (ii) Long-term growth: weight, height or head circumference and/or proportion of infants who remain below the 10th percentile for the index population's distribution assessed at intervals from six months of age.
- Neurodevelopment: death or severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component will be analysed individually as well as part of the composite outcome.
- 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 phototherapy for hyperbilirubinaemia (days).
- Duration of hospital stay (days).
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal Group (http://neonatal.cochrane.org/).
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 12), MEDLINE (1980 to December 2012), EMBASE (1980 to December 2012) and CINAHL (1982 to December 2012) using the following text words and MeSH terms: [Infan*, OR Infant/, OR Preterm, OR Prem*, OR Infant premature/, OR Neonat*, OR New ADJ born, OR New?born, Infant newborn/, OR Very Low Birth Weight, OR VLBW, OR Extremely Low Birth Weight, OR ELBW, OR Infant Very Low Birth Weight/ OR Infant Extremely Low Birth Weight/] AND [Breast feeding, OR Breast feeding/, OR human milk, OR human milk/, OR formula, Infant formula/, OR Trophic feeding, OR minimal enteral nutrition, OR MEN, OR minimal enteral feeding, OR MEF, OR gut priming, OR enteral feed*, OR enteral nutrition/].
The search outputs were limited with the relevant search filters for clinical trials. We did not apply any language restriction.
Searching other resources
We examined reference lists in previous reviews and studies.
We examined the references in studies identified as potentially relevant. We also searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2012), the UK Royal College of Paediatrics and Child Health (2000 to 2012) and the Perinatal Society of Australia and New Zealand (2000 to 2012). We considered trials reported only as abstracts to be eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/).
Selection of studies
Two review authors screened the title and abstract of all studies identified by the above search strategy. We reassessed the full text of any potentially eligible reports and excluded those studies that did not meet all of the inclusion criteria. Review authors discussed any disagreements until consensus was achieved.
Data extraction and management
We used a data collection form to extract relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements with the third author until we reached consensus.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. 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: We categorised the method used to generate the allocation sequence as:
- low risk: any random process e.g. random number table; computer random number generator;
- high risk: any non random process e.g. odd or even date of birth; patient case-record number;
- Allocation concealment: We categorised the method used to conceal the allocation sequence as:
- low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;
- high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;
- Blinding: We assessed blinding of participants, clinicians and care givers, and outcome assessors separately for different outcomes and categorised the methods as:
- low risk;
- high risk;
- Incomplete outcome data: We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:
- low risk: < 20% missing data;
- high risk: > 20% missing data;
Measures of treatment effect
We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CI). We used a fixed-effect model for meta-analysis.
Assessment of heterogeneity
We examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots if more than one trial was included in a meta-analysis. We calculated the I² statistic for statistical heterogeneity. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions or completeness of outcome assessments) in sensitivity analyses.
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
- trials in which most infants were exclusively formula-fed;
- trials in which most infants were at least partially fed with human milk (maternal or donor);
- trials in which most participants were of ELBW (< 1000 grams) or extremely preterm (< 28 weeks);
- trials in which participants were infants with intrauterine growth restriction, or infants with absent or reversed end-diastolic flow velocities detected on antenatal Doppler studies of the fetal aorta or umbilical artery.
Description of studies
We identified 17 articles using the above search strategy.
Nine trials fulfilled the inclusion criteria (Dunn 1988; Meetze 1992; Troche 1995; Becerra 1996; Schanler 1999; McClure 2000; Sáenz de Pipaón 2003; van Elburg 2004; Mosqueda 2008; see table 'Characteristics of included studies').
The included studies were all undertaken since the late 1980s by investigators attached to neonatal units in Europe and North America. Most were small single-centre studies. 754 infants participated in total (range 29 to 190). Most participants were appropriate-for-gestational age VLBW or very preterm infants receiving standard intensive care interventions such as mechanical ventilation and parenteral nutrition. In van Elburg 2004, participants were infants of birth weight less than 2000 grams who were small for gestational age (< 10th percentile for birth weight). We included this study because > 80% of participating infants were VLBW. Most of the other trials specifically excluded infants who were small for gestational age at birth and infants with congenital anomalies, gastrointestinal problems or neurological problems.
Trophic feeding was generally started within the first three days after birth and continued for varying durations; either until infants were judged to be clinically stable (for example following endotracheal extubation or removal of umbilical catheters) or for pre-defined intervals, generally 7 to 10 days after birth. Feeding volumes ranged from about 12 to 24 ml/kg/day. One trial administered milk at a rate of 25 ml/kg/day with no intention to increase this volume for six to eight days (Becerra 1996). Although this rate exceeded our definition of minimal enteral nutrition by 1 ml/kg/day, we made a consensus decision to include the trial.
In most trials, infants received either expressed breast milk or formula milk (diluted or full-strength) or a mixture of breast milk and formula. In two trials, infants received only formula milk (Dunn 1988; Meetze 1992). Control infants received no enteral nutrition for at least one week after birth. Infants in both comparison groups received standard parenteral nutrition during the trial period.
In most trials, milk was administered by intermittent bolus gavage feeds via oro or nasogastric tube. In Schanler 1999, participating infants were also allocated to either bolus or continuous feeding using a factorial design. In Troche 1995, infants weighing < 800 grams at birth received feeds via a continuous infusion whereas those weighing > 800 grams at birth received intermittent bolus feeds.
Most trials assessed feed intolerance (variously defined) and incidence of necrotising enterocolitis. Short-term growth parameters were reported in a variety of ways, most commonly time to regain birth weight and weight gain during the neonatal period (either as median and range or as mean and standard deviation). Most reports also gave information on adverse outcomes including mortality. None of the trials reported long-term growth and neurodevelopmental outcomes for surviving infants.
Risk of bias in included studies
Most of the trials had some methodological weaknesses. In four trials it was unclear whether allocation was concealed. Care givers were not blinded to treatment group in any trial. Few trials undertook blinded assessments for any of the outcomes, and several of the trials did not include results for all infants randomised (see table 'Characteristics of included studies').
Effects of interventions
Feed intolerance: time to establish full enteral feeding (outcome 1.1; eight trials)
Meta-analysis of data from six trials that reported mean and standard deviation (SD) did not detect a statistically significant effect: mean difference (MD) -1.05 (95% confidence interval (CI) -2.61 to 0.51) days. The meta-analysis contained significant statistical heterogeneity in (I² = 73%) ( Analysis 1.1).
Necrotising enterocolitis (outcome 1.2; nine trials)
Meta-analysis did not detect a statistically significant effect: typical risk ratio (RR) 1.07 (95% CI 0.67 to 1.70); typical risk difference (RD) 0.01 (95% CI -0.03 to 0.05). There was no evidence of heterogeneity (I² = 0%) ( Analysis 1.2).
Mortality (outcome 1.3; eight trials)
Meta-analysis did not detect a statistically significant effect: typical RR 0.66 (95% CI 0.41 to 1.07); typical RD -0.04 (95% CI -0.10 to 0.01). There was no evidence of heterogeneity (I² = 0%) ( Analysis 1.3).
Growth (outcome 1.4; eight trials)
None of the trials reported a statistically significant difference in the time to regain birth weight. Meta-analysis of five trials with data as mean and SD: MD -0.01 (95% CI -0.96 to 0.95) days. There was no evidence of statistical heterogeneity (I² = 23%) ( Analysis 1.4).
McClure 2000 reported that the average rate of weight gain and head circumference gain during the six weeks after birth was borderline significantly higher in infants who had received trophic feeds:
- Weight: reported MD 130 (95% CI 1 to 250) grams/week.
- Head circumference: reported MD 0.7 (95% CI 0.1 to 1.3) cm/week
Mosqueda 2008 reported no statistically significant difference in rates of weight gain during the trial period: MD -7.3 (95% CI -19.2 to 4.6) grams/week.
Sáenz de Pipaón 2003 reported that the weight above birth weight attained by day 21 was not statistically significantly different (188 grams versus 190 grams).
Troche 1995 reported that infants in the trophic feeding group had a higher increase in weight over birth weight to day 30 (223 (SD 125) versus 95 (SD 161) grams).
Meetze 1992 reported no statistically significant difference in weight gain between the groups at day 30: 264 (SD 126) grams versus 213 (SD 142) grams. Increases in head circumference, length and mid-arm circumference were reported to be similar for both groups.
Dunn 1988 measured growth throughout the study period up until 60 days of life and did not detect any significant differences between the two groups.
Long-term growth parameters were not reported by any of the trials.
None of the trials assessed neurodevelopmental outcomes.
Incidence of invasive infection (outcome 1.5; four trials)
Meta-analysis of three trials did not detect a statistically significant difference: typical RR 1.06 (95% CI 0.72 to 1.56); typical RD 0.02 (95% CI -0.10 to 0.13). There was no evidence of heterogeneity (I² = 25%) ( Analysis 1.5).
McClure 2000 reported that infants in the minimal enteral nutrition group had a statistically significantly lower mean number of episodes of "culture-confirmed sepsis" (0.5 versus 1.2 in control group). These data could not be included in the meta-analysis.
Duration of phototherapy (days) (outcome 1.6; three trials)
Meta-analysis did not detect a statistically significant effect: MD 0.35 (95% CI -0.29 to 0.99) days ( Analysis 1.6).
Duration of hospital stay (outcome 1.7; five trials)
Meta-analysis of four trials that reported data as mean and SD did not detect a statistically significant effect: MD -3.9 (95% CI -11.5 to 3.8) days ( Analysis 1.7). There was evidence of borderline statistical heterogeneity (I² = 48%).
One trial that reported median and range data did not find a statistically significant difference: 81 days versus 79.5 days (Mosqueda 2008).
- Infants at least partially fed with breast milk: Subgroup data were not available.
- Extremely low birth weight (ELBW) or extremely preterm infants: One trial restricted participation to ELBW infants (Mosqueda 2008). In the other trials, it is likely that less than one-third of all participants were ELBW or extremely preterm but subgroup data were not available.
- Infants with intrauterine growth restriction or infants with absent or reversed end-diastolic flow velocities (AREDFV): In those trials where birth weight < 10th percentile was not an exclusion criterion, subgroup data were not available. One trial restricted participation to infants who were small for gestational age (birth weight < 10th percentile for reference population) (van Elburg 2004).
Summary of main results
The available data from randomised controlled trials do not provide evidence that early trophic feeding compared to enteral fasting confers any substantial benefits for very preterm or very low birth weight (VLBW) infants. Although some trials reported that minimal enteral nutrition reduced the time taken to establish full enteral feeds, meta-analysis of all of the available data did not detect a statistically significant effect.
The trial data do not suggest that minimal enteral nutrition is associated with important harms. Meta-analyses did not detect statistically significant effects on the incidence of necrotising enterocolitis, invasive infection or all-cause mortality. Only limited data on growth outcomes were found. Trials found inconsistent effects on short-term growth and meta-analysis did not reveal a significant difference in the time taken to regain birth weight. The clinical importance of any short-term effects is unclear as no long-term growth or developmental outcomes were assessed.
Overall completeness and applicability of evidence
These findings should be applied with caution. Although we did not find evidence of an effect on feed intolerance, the existence of substantial statistical heterogeneity in the meta-analysis limits the validity of this finding. The heterogeneity was not explained by differences between trials in methodological quality or the type of intervention or participants. It may be that variations in enteral feeding protocols and practices contributed to heterogeneity.
These findings may not be applicable to some infants at highest risk of developing feed intolerance or necrotising enterocolitis. Only a minority of participants in the included trials were extremely low birth weight (ELBW) or extremely preterm infants or had evidence of intrauterine growth restriction. None of the trials specifically recruited infants with absent or reversed end-diastolic flow velocities on Doppler ultrasound of the umbilical arteries. Furthermore, the risk-benefit balance of enteral feeding strategies may differ between breast milk-fed and formula-fed very preterm or VLBW infants. One study reported that mothers who expressed breast milk for early trophic feeding were more likely to continue to provide breast milk as the ongoing principal form of nutrition for their infants (Schanler 1999). Further study to confirm and define the mechanism of this association is merited given that feeding with breast milk compared to formula reduces the risk of necrotising enterocolitis in very preterm or VLBW infants (Quigley 2007).
It is also unclear whether the findings can be applied to infants who receive continuous infusion of milk feeds as all of the infants in the included trials received enteral feeds as interval boluses. A recently described issue is that bolus administration of volumes up to 0.5 ml results in substantial retention of milk within standard gastric feeding tubes (which will then be aspirated prior to the next feed). Consequently, infants will not actually receive any milk intragastrically unless trophic feeding is delivered continuously (McHale 2010). Randomised controlled trials have reported conflicting findings about the effect on continuous enteral infusion on feed tolerance in very preterm and VLBW infants (Premji 2011).
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 care givers and clinical assessors to the nature of the intervention (Figure 1). This may be an important source of bias particularly in trials that did not use prespecified definitions of feed intolerance that mandated interrupting or ceasing feed volume advancement. Care givers or clinicians who were aware of the treatment group may have defined feed intolerance subjectively and differentially. Any surveillance and ascertainment biases secondary to the lack of blinding are more likely to have caused an over-estimation of the incidence of feed intolerance or necrotising enterocolitis in infants who received minimal enteral nutrition.
|Figure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
Implications for practice
The available trial data do not provide strong evidence that early trophic feeding has important effects on feed intolerance, growth or development. There is no evidence that trophic feeding has adverse effects. For necrotising enterocolitis, the lower and bounds of the 95% CI of the number needed to treat for an additional harmful outcome (NNTH) estimate are consistent with either five more cases or three fewer cases in every 100 infants who receive early trophic feeding. For mortality, the NNTH 95% CI is consistent with one more case or 10 fewer cases in every 100 infants who receive early trophic feeding.
Implications for research
Any new randomised controlled trials of early trophic feeding versus enteral fasting should aim to ensure the participation of extremely low birth weight (ELBW) and extremely preterm infants as well as infants with evidence of compromised intrauterine growth so that findings are applicable to these infants at highest risk of necrotising enterocolitis. Undertaking trials of feeding interventions in this population is problematic (Tyson 2007). It is difficult to perform a pragmatic trial that will ensure that care givers and investigators are unaware of the allocated feeding regimen. 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. Trials should also aim to assess more objective outcomes, principally mortality and long-term growth and development.
We are grateful to Ms Bethan Carter for developing and running the electronic search.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Last assessed as up-to-date: 27 December 2012.
Protocol first published: Issue 4, 1997
Review first published: Issue 4, 1997
Contributions of authors
The review authors developed the protocol, undertook the literature search, appraised the articles, extracted and entered the data, and completed the review jointly.
Declarations of interest
Sources of support
- Centre for Reviews and Dissemination, University of York, UK.
- NIHR, UK.
- Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.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
Medical Subject Headings (MeSH)
Adaptation, Physiological; Child Development [*physiology]; Enteral Nutrition [adverse effects; *methods]; Enterocolitis, Necrotizing [prevention & control]; Infant Formula; Infant, Premature; Infant, Very Low Birth Weight [growth & development; *physiology]; Milk; Milk, Human; Parenteral Nutrition [adverse effects; methods]; Randomized Controlled Trials as Topic
MeSH check words
Animals; Humans; Infant, Newborn
* Indicates the major publication for the study