1. Objectives

To evaluate the delayed introduction of progressive enteral feeds in very preterm or very low birth weight (VLBW) infants for the prevention of necrotising enterocolitis (NEC), mortality and other morbidities

2. How studies were identified

The following databases were searched in September 2014:

• CENTRAL (The Cochrane Library 2014, Issue 8)
• MEDLINE
• EMBASE
• CINAHL
• ClinicalTrials.gov
• Current Controlled Trials

Reference lists and conference proceedings were also searched

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including cluster-randomized trials and quasi-randomized trials

3.2 Study participants

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

3.3 Interventions

Delayed introduction (≥4 days post-birth) of progressive enteral feeds compared with earlier introduction of enteral feeds (<4 days post-birth), with both groups receiving the same milk, feeding route and mode, and rate of feed volume advancement

(Progressive enteral feeds were defined as the intention to advance feed volumes to greater than minimal enteral nutrition levels [ >24 mL/kg/day] within five days of feed initiation or by one week post-birth)

3.4 Primary outcomes

• NEC confirmed by surgical or autopsy diagnosis or by ≥2 of the following: i) abdominal radiograph showing pneumatosis intestinalis or gas in the portal venous system or free air in the abdomen; ii) abdominal distension with abdominal radiograph with gaseous distension or frothy appearance of bowel lumen (or both); iii) blood in the stool; and iv) lethargy, hypotonia or apnoea (or a combination of these)
• All-cause mortality during the neonatal period and prior to hospital discharge

Secondary outcomes included growth (time to regain birth weight, rates of growth up to six months of age, long-term growth after six months of age), neurodevelopment (death or severe neurodevelopmental disability, neurodevelopmental scores from 12 months of age, cognitive and educational outcomes from five years of age), time to establish enteral feeding, time to establish oral feeding, feed intolerance (defined as a requirement to cease enteral feeds), invasive infection, and duration of hospital stay

4. Main results

4.1 Included studies

Nine randomized controlled trials, enrolling 1106 infants, were included in this review

• Four of the nine studies included infants who did not meet the inclusion criteria (VLBW or very preterm); however, as the majority of infants in these trials were <1500 g, a consensus decision was made by the review authors to include the studies
• Eight studies defined delayed introduction of enteral feeding as between four and seven days post-birth and one trial defined delayed introduction as day 10 following birth; in all trials early introduction of enteral feeding was from day one to four post-birth
• Enteral feeds were given by gavage at one- or two-hourly intervals in eight trials, and in one trial, infants received feeds by continuous intragastric infusion. Infants received a combination of breast milk and formula in seven trials, and formula alone in two trials
• Specific criteria for the advancement of enteral feed volumes (an increase of 15 to 30 mL/day) and interrupting enteral feeding were stated in all but one trial
• Four trials specifically recruited infants at risk of developing NEC due to intrauterine growth restriction and abnormal fetal circulatory distribution or flow

4.2 Study settings

• Colombia, Greece, Iran, Israel, the United States of America (3 trials), Qatar, and a multi-site study in Ireland and the United Kingdom of Great Britain and Northern Ireland
• Most trials were conducted in the 2000’s, with infants receiving modern standards of antenatal care such as antenatal corticosteroids and exogenous surfactant

4.3 Study settings

How the data were analysed
Delayed introduction of progressive enteral feeds was compared to earlier introduction of enteral feeds. Dichotomous data were summarized using risk ratios (RR), while continuous data were summarized using mean differences (MD), with corresponding 95% confidence intervals (CI). If substantial heterogeneity was identified (I²>50%), sensitivity analyses were performed to explore potential sources, investigating factors such as study design and rates of attrition. The following subgroup analyses were also planned:

• Formula-fed infants
• Breastfed (maternal or donor milk) infants
• Extremely low birth weight (<1000 g) or extremely preterm (<28 weeks’ gestation) infants
• Infants with intrauterine growth restriction, or infants with absent or reversed end-diastolic flow velocities

Results
Necrotising enterocolitis
Pooled analysis of eight trials involving 1092 infants found no statistically significant difference in the risk of NEC between delayed and early introduction of progressive enteral feeding (RR 0.93, 95% CI [0.64 to 1.34]). In subgroup analyses of formula-fed infants and infants with intrauterine growth restriction and abnormal flow velocities, no statistically significant differences between treatment groups were found.

Mortality prior to discharge
Meta-analysis of seven trials involving 967 infants failed to demonstrate an effect of delayed introduction of progressive enteral feeding on mortality prior to discharge (RR 1.18, 95% CI [0.75 to 1.88]). No statistically significant differences between treatment groups were found in subgroup analyses of formula-fed infants and infants with intrauterine growth restriction and abnormal flow velocities.

Additional outcomes
Time to regain birth weight was not different between delayed and early feeding groups in two trials, and in another two trials the rate of weight gain was not different between groups. Median time to establish full enteral feeding was reported to be two to five days later with delayed introduction of enteral feeds in seven of the nine trials, but results were not provided with the data required for quantitative meta-analysis. Pooled analysis of two trials involving 288 infants found no difference in feed intolerance between groups (RR 0.84, 95% CI [0.62 to 1.15]). The incidence of invasive infection was also not significantly different between treatment groups (RR 1.27, 95% CI [0.95 to 1.70], 2 trials/457 infants). The duration of hospital stay was increased by a statistically significant 2.11 days on average among infants receiving delayed introduction of enteral feeding (95% CI [0.31 to 3.90 days], 3 trials/346 infants). No other pre-specified outcomes were reported on.

5. Additional author observations*

While the overall methodological quality of the included trials was reasonable, blinding of clinical assessments was not possible, and five of the nine trials had unclear methods of allocation concealment. Most of the trials included in this review were conducted in clinically modern settings in middle- or high-income countries, reducing the applicability of the findings to low-income countries. The findings of this review also may not be applicable to infants receiving continuous infusion of intragastric feeds, as most participating infants received enteral feeds as interval gastric boluses. In addition to being relevant to current clinical practice in middle- and high-income countries, the findings of this review are also applicable to infants at high risk of NEC due to intrauterine growth restriction or abnormal fetal circulatory distribution or flow, as four of the nine trials recruited infants with these conditions.

Current evidence does not support the use of delayed introduction of progressive enteral feeds to prevent NEC or mortality in VLBW and very preterm infants, or in infants with intrauterine growth restriction or abnormal fetal circulatory distribution or flow. Time to establish full enteral feeding was, however, increased by several days with delayed introduction of enteral feeds, although it is unknown whether this effect is clinically important. In addition, pooled analysis demonstrated an increased hospital stay in infants receiving delayed introduction of enteral feeds.

Further high quality trials in this area are needed to evaluate the effects of delayed versus early introduction of enteral feeds in extremely low birth weight and extremely preterm infants. For VLBW or very preterm infants, trials comparing exclusive enteral feeding from birth to gradual introduction are warranted.