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

  • Review
  • Intervention

Authors


Abstract

Background

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

Objectives

To determine the effect of delayed introduction of progressive enteral feeds on the incidence of necrotising enterocolitis, mortality and other morbidities in very preterm or very low birth weight infants.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), CINAHL (1982 to April 2013), conference proceedings, and previous reviews.

Selection criteria

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

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group, with separate evaluation of trial quality and data extraction by two review authors.

Main results

We identified seven randomised controlled trials in which a total of 964 infants participated. Few participants were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 g). The trials defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth. Meta-analyses did not detect statistically significant effects on the risk of NEC (typical risk ratio (RR) 0.92 (95% confidence interval (CI) 0.64 to 1.34) or all-cause mortality (typical RR 1.26 (95% CI 0.78 to 2.01)). Three of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials did not find any statistically significant effects on the risk of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported median difference two to four days).

Authors' conclusions

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

Résumé

Introduction tardive de l'alimentation entérale progressive pour prévenir l'entérocolite nécrosante chez les nouveau-nés de très faible poids de naissance

Contexte

L'introduction d'une alimentation par voie entérale chez les nouveau-nés très prématurés (< 32 semaines) ou de très faible poids de naissance (< 1500 g) est souvent retardée de quelques jours ou plus après la naissance en raison d'inquiétudes que l'introduction précoce ne soit pas tolérée et accroisse le risque d'entérocolite nécrosante. Cependant, le report de l'alimentation par voie entérale pourrait diminuer l'adaptation fonctionnelle du tractus gastro-intestinal et prolonger le besoin d'alimentation parentérale avec les risques infectieux et métaboliques qui l'accompagnent.

Objectifs

Déterminer l'effet de l'introduction tardive de la nutrition entérale progressive sur l'incidence de l'entérocolite nécrosante, de la mortalité et d'autres pathologies chez les nouveau-nés très prématurés ou de très faible poids de naissance.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre Cochrane des essais contrôlés (CENTRAL, The Cochrane Library, 2013, numéro 3), MEDLINE (de 1966 à avril 2013), EMBASE (de 1980 à avril 2013), CINAHL (de 1982 à avril 2013), les actes de conférence et les revues antérieures.

Critères de sélection

Des essais contrôlés randomisés ou quasi-randomisés évaluant l'effet de l'introduction tardive (plus de quatre jours après la naissance) de l'alimentation entérale progressive par rapport à son introduction précoce sur l'incidence de la NEC, de la mortalité et d'autres pathologies chez les nouveau-nés très prématurés ou de très faible poids de naissance.

Recueil et analyse des données

Nous avons extrait les données en utilisant les méthodes standard du Groupe thématique Cochrane sur la néonatologie avec une évaluation de la qualité des essais et une extraction des données réalisées séparément par deux auteurs de la revue.

Résultats Principaux

Nous avons identifié sept essais contrôlés randomisés auxquels ont participé un total de 964 nouveau-nés. Peu de participants étaient des nourrissons extrêmement prématurés (< 28 semaines) ou de poids de naissance extrêmement faible (< 1000 g). Les essais avaient défini l'introduction tardive comme s'opérant plus de cinq à sept jours après la naissance et l'introduction précoce comme réalisée moins de quatre jours après la naissance. Les méta-analyses n'ont pas décelé d'effets statistiquement significatifs sur le risque de ECN (risque relatif (RR) de 0,92 ; intervalle de confiance (IC) à 95 % de 0,64 à 1,34) ou de mortalité toutes causes (RR typique 1,26 ; IC 95% 0,78 à 2,01). Trois des essais avaient limité la participation aux nouveau-nés présentant un retard de croissance et chez qui l'échographie Doppler avait montré une distribution ou un débit anormal de la circulation fœtale. Les analyses en sous-groupes planifiées de ces essais n'ont pas trouvé d'effets statistiquement significatifs sur le risque de ECN ou de mortalité toutes causes. Chez les nourrissons dont l'introduction de l'alimentation entérale avait été retardée, la mise en place d'une pleine alimentation entérale avait pris plus de temps (différence médiane rapportée de deux à quatre jours).

Conclusions des auteurs

Les données disponibles provenant d'essais contrôlés randomisés suggèrent que le fait de retarder l'introduction de l'alimentation entérale progressive au-delà de quatre jours après la naissance n'affecte pas le risque d'ECN pour les nouveau-nés très prématurés ou de très faible poids de naissance, y compris chez ceux présentant un retard de croissance. Retarder l'introduction de l'alimentation entérale progressive a pour résultat de retarder de quelques jours l'établissement d'une pleine alimentation entérale, mais l'importance clinique de cet effet n'est pas claire. L'applicabilité de ces résultats aux nouveau-nés extrêmement prématurés ou de poids de naissance extrêmement faible demeure incertaine. Il pourrait être nécessaire de réaliser de nouveaux essais contrôlés randomisés dans cette population.

Plain language summary

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

Very preterm (< 32 weeks) or very low birth weight infants (< 1500 g) are at risk of developing a severe bowel disorder called necrotising enterocolitis. It is thought that one possible way to prevent this condition is to delay the introduction of milk feeds until several days (or longer) after birth. We found seven trials involving 964 infants that assessed the effect of delayed rather than early introduction of milk feeds for very preterm or very low birth weight infants. Data from these trials did not provide any evidence that delaying enteral feeding reduces the risk of necrotising enterocolitis.

Résumé simplifié

Introduction tardive de l'alimentation entérale progressive pour prévenir l'entérocolite nécrosante chez les nouveau-nés de très faible poids de naissance

Il n'y a pas de preuve que l'introduction tardive de l'alimentation entérale progressive prévienne l'entérocolite nécrosante chez les nouveau-nés de très faible poids de naissance

Les nouveau-nés très prématurés (< 32 semaines) ou de très faible poids de naissance (< 1500 g) sont exposés au risque de développer une maladie intestinale grave appelée entérocolite nécrosante. On pense qu'une façon possible de prévenir cette affection est de n'introduire l'alimentation au lait que quelques jours (ou plus) après la naissance. Nous avons trouvé sept essais, impliquant au total 964 nouveau-nés, qui avaient évalué l'effet de l'introduction tardive plutôt que précoce de l'alimentation au lait chez les nouveau-nés très prématurés ou de très faible poids de naissance. Les données de ces essais n'ont fourni aucune preuve que le report de l'alimentation entérale réduise le risque d'entérocolite nécrosante.

Notes de traduction

Traduit par: French Cochrane Centre 3rd June, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Description of the condition

Necrotising enterocolitis (NEC) is an important cause of morbidity, mortality and neuro-disability in very preterm (< 32 weeks) or very low birth weight (VLBW: < 1500 g) infants. Extremely low birth weight (ELBW: < 1000 g) and extremely preterm (< 28 weeks) infants are at greatest risk (Bisquera 2002; Holman 2006; Rees 2007; Berrington 2012). Intrauterine growth restriction may be an additional specific risk factor, especially if associated with circulatory redistribution demonstrated by absent or reversed end-diastolic flow velocities in antenatal Doppler studies of the fetal aorta or umbilical artery (Bernstein 2000; Garite 2004; Dorling 2005; Kamoji 2008).

Description of the intervention

Most very preterm or VLBW infants who develop NEC have received enteral milk feeds. Evidence exists that feeding with artificial formula rather than human milk increases the risk (Quigley 2007). The timing of the introduction and the rate of progression of enteral feed volumes may also be modifiable risk factors for the development of NEC (Brown 1978; Uauy 1991; Henderson 2009). Data from observational studies suggest that using feeding regimens that include delaying the introduction of progressive enteral feeds for about five to seven days after birth reduces the risk of NEC (Patole 2005; Hay 2008).

Why it is important to do this review

In current clinical practice, the introduction of progressive enteral feeds for very preterm or VLBW infants is often preceded by a period of enteral fasting or "minimal enteral nutrition" (Boyle 2004; Patole 2004; Hay 2008; Klingenberg 2012). However, there may also be potential disadvantages associated with delaying the introduction of progressive enteral feeds. Because gastrointestinal hormone secretion and motility are stimulated by enteral milk, delayed enteral feeding could diminish the functional adaptation of the gastrointestinal tract (Berseth 1990; Burrin 2002). Prolonging the duration of use of parenteral nutrition may be associated with infectious and metabolic complications that increase mortality and morbidity, prolong hospital stay, and adversely affect growth and development (Flidel-Rimon 2004; Stoll 2004). It has been argued that the risk of NEC should not be considered in isolation of these other potential clinical outcomes when determining feeding policies and practice for very preterm or VLBW infants (Flidel-Rimon 2006; Hay 2008; Hartel 2009).

This review focuses on the comparison of delayed versus earlier introduction of progressive enteral feeding; that is, advancing the volume of milk feeds beyond minimal enteral nutrition levels. We address the effect of minimal enteral nutrition, the early introduction of small volume enteral feeds (up to 24 mL/kg/day) without advancing the feed volumes for at least five days versus enteral fasting in another Cochrane review (Bombell 2009).

Objectives

To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants.

Methods

Criteria for considering studies for this review

Types of studies

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

Types of participants

VLBW (< 1500 g) or very preterm (< 32 weeks) newborn infants.

Types of interventions

Delayed introduction (> four days after birth) of progressive enteral feeds versus earlier introduction of enteral feeds. Progressive enteral feeding is defined as the intention to advance feed volumes in excess of minimal enteral nutrition levels (24 mL/kg/day) within five days of commencement or by one week after birth.

Infants in each group should have received the same type of milk (breast milk or formula), the same route and mode of feeding (intragastric or transpyloric, bolus gavage or continuous) and the same rate of feed volume advancement in both groups.

Types of outcome measures

Primary outcomes

1. NEC confirmed by at least two of the following features:

  • abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen;

  • abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both);

  • blood in stool;

  • lethargy, hypotonia, or apnoea (or combination of these).

Or by a diagnosis confirmed at surgery or autopsy (Walsh 1986).

2. All-cause mortality during the neonatal period and prior to hospital discharge.

Secondary outcomes

3. Growth:
(i) Time to regain birth weight and subsequent rates of weight gain, linear growth, head growth, or skinfold thickness growth up to six months (corrected for preterm birth).
(ii) Long-term growth: weight, height, or head circumference (and/or proportion of infants who remain below the 10th percentile for the index population's distribution) assessed at intervals from six months of age.

4. Neurodevelopment:
(i) Death or severe neurodevelopmental disability defined as any one or combination of the following: non-ambulant cerebral palsy, developmental delay (developmental quotient less than 70), auditory and visual impairment. Each component will be analysed individually as well as part of the composite outcome.
(ii) Neurodevelopmental scores in survivors aged greater than, or equal to, 12 months of age measured using validated assessment tools.
(iii) Cognitive and educational outcomes in survivors aged more than five years old.

5. Time to establish full enteral feeding (independently of parenteral nutrition).

6. Time to establish oral feeding (independently of parenteral nutrition and/or enteral tube feeding).

7. Feed intolerance (defined as a requirement to cease enteral feeds).

8. Incidence of invasive infection as determined by culture of bacteria or fungus from blood, cerebrospinal fluid, urine, or from a normally sterile body space.

9. Duration of hospital stay (days).

Search methods for identification of studies

We used the standard search strategy of the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/).

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, 2013, Issue 3), MEDLINE (1966 to April 2013), EMBASE (1980 to April 2013), and CINAHL (1982 to April 2013) using a combination of the following text words and MeSH terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth Weight OR Infant, Very Low Birth Weight/ OR infan* OR neonat* OR preterm OR prem*] AND "Infant-Nutrition"/ all subheadings OR Infant Formula OR milk OR formula OR trophic feeding OR minimal enteral nutrition OR gut priming]. The search outputs were limited with the relevant search filters for clinical trials as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). No language restrictions were applied.

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

Searching other resources

We examined the references in all studies identified as potentially relevant.

We searched the abstracts from the annual meetings of the Pediatric Academic Societies (1993 to 2012), the European Society for Pediatric Research (1995 to 2012), the UK Royal College of Paediatrics and Child Health (2000 to 2012), and the Perinatal Society of Australia and New Zealand (2000 to 2012). Trials reported only as abstracts were eligible if sufficient information was available from the report, or from contact with the authors, to fulfil the inclusion criteria.

Data collection and analysis

We used the standard methods of the Cochrane Neonatal Review Group (http://neonatal.cochrane.org/).

Selection of studies

Two review authors screened the title and abstract of all studies identified by the above search strategy. We assessed the full text of any potentially eligible reports and those studies that did not meet all of the inclusion criteria were excluded. We discussed any disagreements until consensus was achieved.

Data extraction and management

We used a data collection form to aid extraction of relevant information from each included study. Two review authors extracted the data separately. We discussed any disagreements until consensus was achieved. We contacted the investigators for further information if data from the trial reports were insufficient.

Assessment of risk of bias in included studies

We used the criteria and standard methods of the Cochrane Neonatal Review Group to assess the methodological quality of any included trials. Additional information from the trial authors was requested to clarify methodology and results as necessary. We evaluated and reported the following issues in the 'Risk of bias' tables:

  1. Sequence generation: We categorised the method used to generate the allocation sequence as:

    1. low risk: any random process e.g. random number table; computer random number generator;

    2. high risk: any non random process e.g. odd or even date of birth; patient case-record number);

    3. unclear.

  2. Allocation concealment: We categorised the method used to conceal the allocation sequence as:

    1. low risk: e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes;

    2. high risk: open random allocation; unsealed or non-opaque envelopes, alternation; date of birth;

    3. unclear.

  3. Blinding: We assessed blinding of participants, clinicians and caregivers, and outcome assessors separately for different outcomes and categorised the methods as:

    1. low risk;

    2. high risk;

    3. unclear.

  4. Incomplete outcome data: We described the completeness of data including attrition and exclusions from the analysis for each outcome and any reasons for attrition or exclusion where reported. We assessed whether missing data were balanced across groups or were related to outcomes. Where sufficient information was reported or supplied by the trial authors, we re-included missing data in the analyses. We categorised completeness as:

    1. low risk: < 20% missing data;

    2. high risk: > 20% missing data;

    3. unclear.

Measures of treatment effect

We calculated risk ratio (RR) and risk difference (RD) for dichotomous data and mean difference (MD) for continuous data, with respective 95% confidence intervals (CI). We planned to determine the number needed to treat for benefit or harm for any statistically significant differences in the RD.

Unit of analysis issues

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

Assessment of heterogeneity

If more than one trial was included in a meta-analysis, we examined the treatment effects of individual trials and heterogeneity between trial results by inspecting the forest plots. We calculated the I² statistic for each analysis to quantify inconsistency across studies and describe the percentage of variability in effect estimates that may be due to heterogeneity rather than sampling error. If substantial (I² > 50%) heterogeneity was detected, we explored the possible causes (for example, differences in study design, participants, interventions, or completeness of outcome assessments) in sensitivity analyses.

Data synthesis

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

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses:

  1. trials in which most infants were exclusively formula-fed;

  2. trials in which most infants were at least partially fed with human milk (maternal or donor);

  3. trials in which most participants were of ELBW (< 1000 g) or extremely preterm (< 28 weeks);

  4. trials in which participants were infants with intrauterine growth restriction, or infants with absent or reversed end-diastolic flow velocities detected on antenatal Doppler studies of the fetal aorta or umbilical artery.

Results

Description of studies

We identified 13 reports for screening.

Included studies

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

Population

A total of 964 infants participated in the included trials.

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

  • Ostertag 1986; VLBW infants assessed to be at high risk of developing NEC (N = 38).

  • Khayata 1987; VLBW infants (N = 12).

  • Davey 1994; Clinically stable preterm infants of birth weight < 2000 g who had a low umbilical artery catheter in situ (N = 62). Since most participants were of birth weight < 1500 g or gestational age < 32 weeks, a consensus decision to include the trial was made.

The four more recent and larger trials were performed within the past 10 years.

  • Karagianni 2010: single-centre study in Greece, infants < 35 weeks' gestation with a birth weight < 10th percentile and evidence of abnormal fetal blood flow patterns on Doppler ultrasound of the umbilical artery (N = 84).

  • Leaf 2012: 54-centre trial in the UK and Ireland, infants i) < 35 weeks' gestation, (ii) birth weight < 10th percentile, and (iii) evidence of abnormal fetal blood flow patterns on Doppler ultrasound studies (N = 404). Since most participants were of birth weight < 1500 g, a consensus decision to include the trial was made.

  • Pérez 2011: single centre in Columbia, very preterm or VLBW infants (N = 239).

  • Abdelmaaboud 2012: single centre in Qatar, preterm infants with intrauterine growth restriction and abnormal Doppler flow patterns on ultrasound of the umbilical artery (N = 125). Since most participants were of birth weight < 1500 g, a consensus decision to include the trial was made.

Interventions/comparisons

In five trials infants received either breast milk, artificial formula or a combination of the two (Davey 1994; Karagianni 2010; Pérez 2011; Leaf 2012, Abdelmaaboud 2012). Only formula-fed infants participated in two trials (Ostertag 1986; Khayata 1987). Infants received enteral feeds by gavage at one-hourly intervals in all of the trials except Ostertag 1986 where infants received feeds by continuous intragastric infusion. In Ostertag 1986, infants were initially fed with a sterile water infusion slowly progressing to a 2.5% dextrose solution followed by half-strength formula. They reached full-strength formula milk seven days after initiating enteral feeds.

All of the trial protocols, except that of the smallest trial (Khayata 1987), specified criteria and indications for advancing (daily increments of 15 to 20 mL/kg) or interrupting enteral feed (for example, residual gastric contents not > 3 to 5 mL or one-third to one-half of the previous feed volume, frequent vomiting, abdominal distention, or detection of blood in the stools).

Outcomes

Six of the trials reported the incidence of NEC (Bell stage II/III: confirmed radiologically, or at surgery or autopsy). The other reported outcomes included mortality, time to establish full enteral feeding, growth and duration of hospital stay. Only one trial reported the incidence of invasive infection (Leaf 2012).

Excluded studies

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

Risk of bias in included studies

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

Figure 1.

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

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

The other trials had various methodological weaknesses. In three trials, methods to ensure adequate allocation concealment were not described. None of the trials was able to conceal the feeding strategies from parents, caregivers or clinical investigators. The assessment of abdominal radiographs (for diagnosis of NEC) was masked in three trials and in particular this was conducted well in the largest two studies (Pérez 2011; Leaf 2012). Complete or near-complete assessments of the primary outcomes were reported and data were available to undertake intention-to-treat analyses as required.

Effects of interventions

PRIMARY OUTCOMES

Necrotising enterocolitis (Outcome 1.1: six trials)

Meta-analysis did not detect a statistically significant effect: typical RR 0.92 (95% CI 0.64 to 1.34); typical RD -0.01 (95% CI -0.05 to 0.03). There was no statistical evidence of heterogeneity or funnel plot asymmetry (Figure 2; Figure 3).

Figure 2.

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

Figure 3.

Funnel plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.1 Necrotising enterocolitis.

Mortality prior to discharge (Outcome 1.2: five trials)

Meta-analysis did not detect a statistically significant effect: typical RR 1.26 (95% CI 0.78 to 2.01); typical RD 0.02 (95% CI -0.02 to 0.05). There was no statistical evidence of heterogeneity or funnel plot asymmetry (Figure 4; Figure 5).

Figure 4.

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

Figure 5.

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

SECONDARY OUTCOMES

Growth (four trials)

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

  • Davey 1994: 13 days for both groups (range not reported).

  • Abdelmaaboud 2012: 13 days in the delayed group compared to 14 days in the early introduction group (range not reported).

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

Long-term growth parameters were not assessed by any of the trials.

Neurodevelopment

None of the trials assessed neurodevelopmental outcomes.

Time to establish full enteral feeding (five trials)

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

Time to establish full oral feeding

Not reported by any of the trials.

Feed intolerance (Outcome 1.3: two trials)

Meta-analysis of data from Karagianni 2010 and Abdelmaaboud 2012 did not detect a statistically significant difference: typical RR 1.04 (95% CI 0.72 to 1.49); typical RD 0.01 (95% CI -0.12 to 0.14) (Figure 6).

Figure 6.

Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome: 1.3 Feed intolerance.

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

Incidence of invasive infection (Outcome 1.4: one trial)

Leaf 2012 did not detect a statistically significant difference: RR 1.25 (95% CI 0.93 to 1.68); RD 0.07 (95% CI -0.02 to 0.16).

Duration of hospital stay (Outcome 1.5: four trials)

Meta-analysis of data from two trials did not detect a statistically significant effect: MD 1.24 (95% CI -0.67 to 3.14) days (Davey 1994; Pérez 2011). Another two trials did not detect a statistically significant effect but the reports did not provide data to allow quantitative synthesis (Abdelmaaboud 2012; Leaf 2012).

Subgroup analyses
  1. Two trials only recruited exclusively formula-fed infants (Khayata 1987; Ostertag 1986). Only Ostertag 1986 reported the effect on NEC (RR 1.08 (95% CI 0.40 to 2.94; RD 0.02 (95% CI -0.27 to 0.31)) or death (RR 1.44 (95% CI 0.57 to 3.61); RD 0.12 (95% CI -0.18 to 0.42)).

  2. Trials in which most infants were at least partially fed with human milk (maternal or donor): subgroup data not available.

  3. ELBW or extremely preterm infants: none of the trials recruited predominantly ELBW or extremely preterm infants.

  4. Three trials recruited only infants with intrauterine growth restriction and abnormal flow velocities detected on antenatal Doppler studies (Karagianni 2010; Leaf 2012, Abdelmaaboud 2012). Meta-analysis did not detect any statistically significant differences in the incidence of NEC (typical RR 0.87 (95% CI 0.54 to 1.41); typical RD -0.01 (95% CI -0.06 to 0.03)) (Figure 2) or death (typical RR 1.06 (95% CI 0.55 to 2.05); typical RD 0.00 (95% CI -0.04 to 0.05)) (Figure 4).

Discussion

Summary of main results

Seven randomised controlled trials in which a total of 964 infants participated have assessed the effect of delaying the introduction of progressive enteral feeds on the risk of developing NEC and other adverse outcomes in very preterm or VLBW infants. The data from these trials do not provide evidence that delayed introduction affects the risk of NEC or death. Infants who had delayed introduction of feeds achieved full enteral feeding about one to three days later than infants who had earlier introduction. Whether this is associated with important clinical adverse consequences such as a higher rate of nosocomial infection secondary to prolonged use of parenteral nutrition or a longer duration of hospital admission remains unclear.

Overall completeness and applicability of evidence

These data are relevant to current practice since the four largest trials (Karagianni 2010; Pérez 2011; Leaf 2012; Abdelmaaboud 2012), in which 852 infants participated, were conducted during the past 10 years with infants receiving 'modern' perinatal care including exposure to antenatal corticosteroids and exogenous surfactant, interventions which reduce the risk of NEC or death in this population (Roberts 2006; Seger 2009; Soll 2009; Soll 2010). Three of these trials specifically recruited infants thought to be at higher risk of developing NEC due to intra-uterine growth-restriction and abnormal fetal circulatory distribution or flow. This increases the applicability of the findings since this is the population for which most clinical uncertainty and variation in practice with regard to early feeding strategies exists (Boyle 2004). Previously, this population of infants has been specifically excluded from participating in many trials of early enteral feeding practices (Tyson 2007).

Evidence exists that artificial formula feeding increases the risk NEC (Quigley 2007). The risk-benefit balance of enteral feeding strategies may differ between human milk-fed and formula-fed very preterm or VLBW infants. Currently there are insufficient data to comment on whether there is a differential effect of the timing of the introduction of enteral feeds depending on whether infants received human breast milk versus formula. This issue may be clarified when the subgroup data from the largest trial are available (Leaf 2012).

It is also unclear whether the findings can be applied to infants who receive continuous infusion of intragastric feeds, as most of the infants in the included trials received enteral feeds as interval gastric boluses. Randomised controlled trials have reported conflicting findings about the effect on continuous enteral infusion on feed tolerance in very (and especially extremely) low birth weight infants (Premji 2011).

All of the included trials were undertaken in neonatal care centres in middle- or high-income countries. It is unclear how applicable this evidence is to neonatal care practices in low-income countries. Conservative strategies such as delayed introduction of enteral feeds may confer less nutritional disadvantage in settings where adjunctive parenteral nutrition is readily and safely available. In settings with less technologically-developed healthcare provision where parenteral nutrition is not available and where severe infection (diarrhoea, pneumonia, septicaemia) is a much more important cause of mortality and morbidity, the nutritional and immunological advantages of early feeding, particularly with breast milk, may outweigh any risks associated with enteral feeding for very preterm or VLBW infants (Narayanan 1982; de Silva 2004).

Quality of the evidence

The included trials were generally of reasonable methodological quality but, in common with other trials of feeding interventions in this population, it was not possible to mask caregivers and clinical assessors to the nature of the intervention. Although the lack of blinding may have resulted in surveillance and ascertainment biases, this is more likely to have caused an underestimation of the incidence of NEC in infants whose enteral feeding was delayed. The assessment of abdominal X-rays was masked in three studies to ensure that the diagnosis of stage II/III NEC (confirmed by the radiological detection of gas in the bowel wall or portal tract) was not prone to bias. However, since the microbial generation of gas in the bowel wall is substrate dependent, infants who received more enteral milk (substrate) may have been more likely to demonstrate this radiological sign than infants with equally severe bowel disease who had less intraluminal substrate. This "substrate effect" is also more likely to cause under-ascertainment of NEC in the infants whose enteral feeding was delayed (Tyson 2007).

Potential biases in the review process

The definition of delayed introduction of progressive feeds may vary between different subpopulations of very preterm or VLBW infants who have different empiric risks for developing feed intolerance and NEC. The effects of enteral feeding are likely to be very different for a mechanical ventilator or inotrope-dependent infant of birth weight < 700 g compared with a clinically-stable infant of birth weight > 1400 g. For this Cochrane review, delayed introduction was defined as later than four days after birth since some observational studies have found the risk of NEC to be lower when feeds are introduced five to seven days after birth (Patole 2005). For ELBW or extremely preterm infants, it may be more appropriate to define delayed introduction as more than seven days after birth (or even later). Small intestinal motility is poorly organised before about 28 weeks' gestation resulting in a higher risk of feed intolerance. Additionally, enteral feeds are often delayed in this population because of respiratory or metabolic instability or because of other putative risk factors for NEC such as the existence of a patent ductus arteriosus, the use of non-steroidal anti-inflammatory agents, or the presence of a umbilical arterial catheter (Boyle 2004).

Authors' conclusions

Implications for practice

The available data from randomised controlled trials do not provide evidence that delaying the introduction of progressive enteral feeds beyond four days after birth affects the risk of NEC, mortality, and other morbidities in very preterm or VLBW infants. Delaying the introduction of progressive enteral feeds may result in two to four days delay in establishing full enteral feeds but the long-term clinical importance of these effects is unclear. Subgroup analyses of trials in which participating infants had evidence of intra-uterine growth restriction or abnormal circulatory distribution or flow did not find any statistically significant effects. However, only limited data are available on the effect of this intervention on outcomes for extremely preterm or ELBW infants. Although current practice tends to favour a conservative approach to enteral feeding in these populations, it also needs to be considered that there are other possible consequences of delayed introduction of enteral feeds such as prolonging the use of parenteral nutrition that may be associated with adverse clinical outcomes.

Implications for research

Further randomised controlled trials could provide more precise estimates of the effects of delaying the introduction of progressive enteral feeding on important outcomes for very preterm or VLBW infants. Trials should aim to ensure the participation of ELBW and extremely preterm infants so that subgroup analyses can be planned for these populations at high risk of NEC. Masking caregivers and investigators to the nature of this intervention is unlikely to be possible. Since the unblinded evaluation of feed intolerance and NEC is subject to surveillance and ascertainment biases, trials could aim to assess more objective outcomes, principally mortality and long-term growth and development. Furthermore, since conservative feeding strategies may result in other "competing outcomes" such as invasive infection that may affect on long-term survival and neuro-disability rates, it is essential that trials are powered and structured to assess these outcomes.

Acknowledgements

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

Data and analyses

Download statistical data

Comparison 1. Delayed versus early introduction of progressive enteral feeding
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Necrotising enterocolitis6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 All trials6950Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.64, 1.34]
1.2 Trials in which participants were infants with intrauterine growth restriction and/or abnormal antenatal Doppler flow velocities3613Risk Ratio (M-H, Fixed, 95% CI)0.87 [0.54, 1.41]
2 Mortality prior to discharge5 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 All trials5825Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.78, 2.01]
2.2 Trials in which participants were infants with intrauterine growth restriction and/or abnormal antenatal Doppler flow velocities2488Risk Ratio (M-H, Fixed, 95% CI)1.06 [0.55, 2.05]
3 Feed intolerance2206Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.72, 1.49]
4 Incidence of invasive infection1397Risk Ratio (M-H, Fixed, 95% CI)1.25 [0.93, 1.68]
5 Duration of hospital admission (postmenstrual weeks at discharge)2286Mean Difference (IV, Fixed, 95% CI)1.24 [-0.67, 3.14]
6 Subgroup analysis with infants < 29 weeks' gestation: mortality186Risk Ratio (M-H, Fixed, 95% CI)1.26 [0.41, 3.81]
7 Subgroup analysis of infants < 29 weeks' gestation: incidence of necrotising enterocolitis186Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.43, 2.54]
Analysis 1.1.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 1 Necrotising enterocolitis.

Analysis 1.2.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 2 Mortality prior to discharge.

Analysis 1.3.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 3 Feed intolerance.

Analysis 1.4.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 4 Incidence of invasive infection.

Analysis 1.5.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 5 Duration of hospital admission (postmenstrual weeks at discharge).

Analysis 1.6.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 6 Subgroup analysis with infants < 29 weeks' gestation: mortality.

Analysis 1.7.

Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 7 Subgroup analysis of infants < 29 weeks' gestation: incidence of necrotising enterocolitis.

What's new

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

DateEventDescription
26 April 2013New citation required but conclusions have not changedUpdated search in April 2013 identified two new trials for inclusion in this review update.
26 April 2013New search has been performedThis updates the review "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" (Morgan 2011).

History

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

DateEventDescription
13 January 2011New search has been performed

This updates the review "Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants" published in the Cochrane Database of Systematic Reviews, Issue 2, 2008 (Bombell 2008).

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

New authorship for this review update.

13 January 2011New citation required and conclusions have changedThe addition of new trial data has increased the total number of participating infants to 600 and modified the implications for practice and research.
2 February 2008New search has been performed

This updates the review "Early versus delayed initiation of progressive enteral feedings for parenterally fed low birth weight or preterm infants" published in the Cochrane Database of Systematic Reviews, Issue 1, 2000 (Kennedy 2000).

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

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

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

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

11 January 2008AmendedConverted to new review format.

Contributions of authors

Jessie Morgan and Lauren Young updated the search, independently determined the eligibility of identified studies, assessed the methodological quality of the included trials, and extracted the relevant information and data. All authors completed the final review.

Declarations of interest

None known.

Sources of support

Internal sources

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

External sources

  • National Institute for Health Research, UK.

  • Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA.

    Editorial support of the Cochrane Neonatal Review Group 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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abdelmaaboud 2012

MethodsRandomised controlled trial
Participants

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

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

Setting: Single centre: Women's Hopsital, Hamad Medical Coordoporation, Qatar

InterventionsEarly introduction of progressive enteral feeds on day 3 (N = 62) versus late introduction of enteral feeds on day 6 (N = 63)
OutcomesIncidence of necrotising enterocolitis (stage II/III), time to reach full enteral feeds (sustained for 72 hours), rates of feed intolerance, mortality and duration of hospital stay
Notes> 90% of participants were VLBW
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated tables
Allocation concealment (selection bias)Unclear riskUnclear
Blinding (performance bias and detection bias)
Clinical assessments
High riskCaregivers not blinded to intervention group
Blinding (performance bias and detection bias)
Radiological assessments
Unclear riskNo information on blinding of radiological assessors to the intervention groups
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data were accounted for

Davey 1994

MethodsRandomised controlled trial
Participants

62 preterm infants with birth weight < 2000 g who were clinically stable and who had an umbilical artery catheter in place. Infants who had a lethal condition or who had received a double-volume exchange transfusion were excluded

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

InterventionsDelayed introduction of enteral feeds (median 5 days; N = 31) vs. earlier introduction (median 2 days; N = 31). Infants received either breast milk or diluted formula (no subgroup data available) Volumes and rates of advancement were the same in both groups
OutcomesDays to regain birth weight, days to full enteral feeding, duration of hospital stay, incidence of NEC and mortality
Notes

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

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSequence generation method not reported
Allocation concealment (selection bias)Low riskSealed opaque envelopes
Blinding (performance bias and detection bias)
Clinical assessments
High riskNot stated but unlikely that caregivers were blinded to intervention groups
Blinding (performance bias and detection bias)
Radiological assessments
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Low riskTwo infants in the early feeding group were excluded from the trial post-randomisation due to protocol violation. All other participants were accounted for

Karagianni 2010

MethodsRandomised controlled trial
Participants

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

Infants with a major congenital anomaly or infection, and infants who received exchange transfusion or inotrope support were excluded from participating

Setting: Neonatology Department, Aristotle University, Thessaloniki, Greece

Interventions

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

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

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

*Unpublished data courtesy of Dr Karagianni

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

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated  sequence
Allocation concealment (selection bias)Low riskOpaque sealed envelopes
Blinding (performance bias and detection bias)
Clinical assessments
High riskCaregivers and clinical assessors not blinded to allocation groups
Blinding (performance bias and detection bias)
Radiological assessments
Unclear riskNo information available about blinding of radiological assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll data have been included in the analyses

Khayata 1987

MethodsRandomised controlled trial
Participants12 VLBW infants
Interventions

Delayed introduction of enteral feeds (day 10 after birth; N = 7) vs. earlier introduction (< 4 days; N = 5)

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

OutcomesGrowth during the first six weeks after birth
NotesThis trial has been reported as an abstract only. Further (unpublished) methodological or outcome data were not available
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Clinical assessments
High riskNot described but unlikely to be blinded
Blinding (performance bias and detection bias)
Radiological assessments
Unclear riskNot described
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot described

Leaf 2012

MethodsRandomised controlled trial
Participants

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

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

or

b) 'cerebral redistribution', defined as occurring when both the umbilical artery pulsatility index is greater than the 95th percentile and the middle cerebral artery pulsatility index is less that the 5th percentile for gestational age (Hershkovitz 2000)

Setting: 54 neonatal care centres in UK and Ireland

InterventionsDelayed (day 5 after birth; N = 202) versus early (day 2 after birth; N = 202) introduction of milk feeds. Infants with a major congenital anomaly, receipt of in-utero transfusion, multi-organ failure or need for inotrope support were excluded. The protocol for advancing feed volumes was the same in both groups
OutcomesDays to full feeds (150 mL/kg/day) sustained for 3 days, incidence of NEC (all stages, and stage II/III), mortality, invasive infection, time to regain birth weight, duration of hospital stay
Notes>90% of participants were VLBW
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated sequence
Allocation concealment (selection bias)Low riskCentral telephone randomisation
Blinding (performance bias and detection bias)
Clinical assessments
High riskCaregivers were not blinded to the allocation groups
Blinding (performance bias and detection bias)
Radiological assessments
Low riskAll cases of NEC were reviewed independently by a committee that were blinded to the study groups
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk2 patients (one from each group) were excluded from the trial after randomisation occurred (error in recruitment and consent withdrawal)

Ostertag 1986

MethodsRandomised controlled trial
Participants

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

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

Interventions

Delayed introduction of enteral feeds (day 7 after birth; N = 20) vs. earlier introduction (day 1; N = 18)

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

OutcomesIncidence of NEC and mortality
NotesFurther details about exclusions after randomisation kindly provided by Dr La Gamma (March 2009)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
Clinical assessments
High riskCaregivers not blinded to allocation groups
Blinding (performance bias and detection bias)
Radiological assessments
Low riskRadiologists reviewing abdominal films were blinded to the group assignments
Incomplete outcome data (attrition bias)
All outcomes
Low riskThree infants died before 7 days after birth. One infant was excluded before day 14 by the investigators because of a feeding protocol violation. We have included all of these infants in the relevant intention to treat analyses

Pérez 2011

  1. a

    NEC: necrotising enterocolitis
    VLBW: very low birth weight
    vs: versus

MethodsRandomised controlled trial
Participants

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

Exclusions included infants with congenital anomalies of the gastrointestinal tract, intrauterine growth restriction and respiratory or haemodynamic instability

Setting: Ramón González Valencia de Bucaramanga University Hospital, Columbia

Interventions

Delayed enteral feeding (day 5 after birth, N = 104) compared to earlier enteral feeding (day 1-2 after birth, N = 135)

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

OutcomesIncidence of NEC, mortality, duration of hospital stay, growth, days to reach full feeds (150 mL/kg/day)
NotesOriginal study published in Spanish
Risk of bias
BiasAuthors' judgementSupport for judgement
Allocation concealment (selection bias)Low risk 
Blinding (performance bias and detection bias)
Clinical assessments
High risk 
Blinding (performance bias and detection bias)
Radiological assessments
Low riskAbdominal X-rays interpreted by radiologist who was independent from the study and blind to the allocation groups
Incomplete outcome data (attrition bias)
All outcomes
Low risk 

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Glass 1984Infants were allocated alternately to either early (first day after birth) or delayed transpyloric enteral feeding. The delayed feeding group commenced enteral nutrition when assessed to be "clinically stable" but this included initiation within four days after birth
Higgs 1974Infants in the delayed progressive enteral feeds group received total parenteral nutrition as a co-intervention
LaGamma 1985This was not a randomised controlled trial
Said 2008Infants in the delayed progressive enteral feeding group received minimal enteral nutrition prior to feed advancement as a co-intervention
Weiler 2006Infants in both groups received some enteral feeds before four days after birth
Wilson 1997Infants in the delayed progressive enteral feeds group also received delayed advancement of parenteral nutrition as a co-intervention