1. Objectives

To evaluate slow rates of enteral feed advancement in very preterm or very low birth weight infants on the incidence of necrotising enterocolitis, mortality and morbidity

2. How studies were identified

The following databases were searched in June 2017:

• CENTRAL (The Cochrane Library 2017, Issue 5)
• MEDLINE
• EMBASE
• CINAHL
• ClinicalTrials.gov
• World Health Organization International Clinical Trials Registry (ICTRP)

Reference lists and conference proceedings were also searched.

3. Criteria for including studies in the review

3.1 Study type

Randomized controlled trials, including quasi-randomized trials

3.2 Study participants

Enterally fed very preterm (<32 weeks’ gestation) or very low birth weight (<1500g) newborn infants

3.3 Interventions

Slow advancement of enteral feeds (≤24 mL/kg/day) compared to faster rates of feed advancement, with feed advancement commencing within five days of enteral feed introduction

(Both treatment and control groups should have received the same type of milk)

3.4 Primary outcomes

• Necrotising enterocolitis 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

Ten randomized controlled trials, enrolling 3753 infants, were included in this review

• Almost three-quarters of all infants were participants in one large multi-centre trial
• Birth weight inclusion criteria ranged from 750 to 1250 g in two trials to 1000 to 2000 g in one trial. The review authors made a consensus decision to include two studies in which most, but not all, participants met the review weight and gestational age inclusion criteria
• Infants born small-for-gestational age (<10th centile of the index population distribution for birth weight) were included in all but one study, and in another study made up most of the population. All participants in one study had antenatal evidence of absent or reversed end-diastolic flow
• Interval bolus intragastric feeding was used in all trials and was initiated within the first seven days post-birth
• Slow advancement rates varied from 15 to 24 mL/kg/day, while faster advancement rates ranged from 30 mL/kg/day up to 40 mL/kg/day
• In three trials, all infants were fed exclusively with expressed breast milk; in one trial, only formula-fed infants were eligible; and in the remaining trials infants were fed expressed breast milk or formula, or a combination of both

4.2 Study settings

• India (4 trials), South Africa (2 trials), Turkey, the United States of America (2 trials), and one multi-centre trial (Ireland and the United Kingdom of Great Britain and Northern Ireland)
• Trials were conducted in neonatal units of hospitals

4.3 Study settings

How the data were analysed
Slow advancement of enteral feed volumes was compared to faster advancement. Dichotomous data were summarized using risk ratios (RR) and risk differences (RD), while continuous data were summarized using mean differences (MD), and corresponding 95% confidence intervals (CI) generated. Where substantial heterogeneity was identified (I²>50%), sensitivity analyses were performed. The following subgroup analyses were planned to further investigate potential sources of heterogeneity:

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

Results
Necrotising enterocolitis
Pooled analysis of ten trials involving 3742 infants revealed no statistically significant difference in the risk of necrotising enterocolitis between infants receiving slow or faster advancement of enteral feeds (RR 1.07, 95% CI [0.83 to 1.39]; RD 0.00, 95% CI [-0.01 to 0.02]). Subgroup analysis of trials in which most infants were extremely preterm or extremely low birth weight also failed to detect a significant effect (RR 1.01, 95% CI [0.74 to 1.38], 5 trials/1299 infants). No evidence of a difference between treatment groups was found in subgroup analyses of infants with intrauterine growth restriction (RR 1.26, 95% CI [0.67 to 2.37], 2 trials/639 infants) or infants with absent or reversed end-diastolic flow velocity (RR 1.59, 95% CI [0.74 to 3.40]). In subgroup analyses by type of milk feed, no statistically significant difference was found between treatment groups (exclusively formula-fed: RR 1.44, 95% CI [0.63 to 3.32], 1 trial/185 infants; partially or exclusively human milk-fed: RR 1.04, 95% CI [0.79 to 1.37], 9 trials/3557 infants).

Mortality
Overall, the risk of mortality was not different between treatment groups in meta-analysis of nine trials involving 3576 infants (RR 1.15, 95% CI [0.93 to 1.42]; RD 0.01, 95% CI [-0.01 to 0.03]). In subgroup analysis of trials in which most infants were extremely preterm or extremely low birth weight, no evidence of a treatment effect was demonstrated (RR 0.83, 95% CI [0.55 to 1.25], 2 trials/200 infants). In subgroup analyses by type of milk feed, there was no difference in mortality between treatment groups (exclusively formula-fed: RD 0.00, 95% CI [-0.02 to 0.02], 1 trial/185 infants; partially or exclusively human milk-fed: RR 1.15, 95% CI [0.93 to 1.42] 8 trials/3391 infants). In subgroup analysis of infants with intrauterine growth restriction, the risk of death was not significantly different between treatment groups (RR 1.78, 95% CI [0.83 to 3.81], 1 trial/53 infants). In one small trial including 30 infants with evidence of absent or reversed end-diastolic flow velocity, no statistically significant difference in mortality was found between treatment groups (RR 7.00, 95% CI [0.39 to 124.83]).

Additional outcomes
Seven of the ten included trials reported on the time to regain birth weight, and in all of these trials, infants receiving a slow rate of enteral feed advancement took statistically significantly longer to do so (MD ranging from 2 to 6 days). In the large multi-centre trial, no difference in weight or head circumference z-scores at hospital discharge was found (weight z-score MD: 0.00, 95% CI [-0.08 to 0.08], 2602 infants; head circumference z-score MD: 0.00, 95% CI [-0.13 to 0.13], 2286 infants). Infants took statistically significantly longer to establish full enteral feeding in all seven of the trials reporting on this outcome (MD ranging from 0.6 to 4.8 days). In pooled analysis of seven trials involving 659 infants, feed intolerance was not different between treatment groups (RR 1.20, 95% CI [0.95 to 1.50]). The risk of invasive infection was borderline statistically significantly greater among infants receiving a slow rate of enteral feed advancement in pooled analysis of seven trials (RR 1.15, 95% CI [1.00 to 1.32], p=0.057; 3392 infants). This translated to an RD of 0.03 (95% CI [-0.00 to 0.05]). In two trials the duration of hospital stay was reported to be significantly greater by 1.5 and six days among infants receiving a slow rate of feed advancement, while in four other studies, no statistically significant difference was found. No other pre-specified outcomes were reported on.

5. Additional author observations*

The overall methodological quality of the included trials was good, with most trials reporting adequate methods of allocation concealment. Only three trials reported blinding the assessment of abdominal radiographs for evidence of necrotising enterocolitis, however. Using the GRADE approach, the quality of the evidence for the primary outcomes was downgraded to moderate due to risk of bias from lack of blinding.

The findings of the review are applicable to most populations at high risk of necrotising enterocolitis, as participants included extremely preterm and extremely low birth weight infants, infants with intrauterine growth restriction, and infants with absent or reversed end-diastolic flow velocity in the fetal umbilical artery. Infants who had severe respiratory distress requiring oxygen supplementation or ventilatory support were also eligible to participate in seven of the ten trials. However, few data were available to investigate the differential effect of slow advancement feeding in formula-fed infants, in whom the risks of necrotising enterocolitis and feed intolerance are greater than infants fed with human milk. The findings of this review may also not be applicable to infants receiving continuous infusion of intragastric feeds, as almost all participating infants received enteral feeds as interval gastric boluses.

Current evidence suggests that the slow advancement of enteral feed volumes does not reduce the risk of necrotising enterocolitis or death in very low birth weight infants, but may increase the time taken to establish full enteral feeding and regain birth weight and may raise the risk of invasive infection.

Further trials of slow advancement feeding are unlikely to provide different effect estimates for the outcomes necrotising enterocolitis, mortality or feed intolerance. Data on longer-term growth and developmental outcomes may become available from follow-up studies of existing trials.