1. Objectives

To evaluate the effect of feeding preterm infants on a responsive basis versus feeding prescribed volumes at scheduled intervals on growth rates, the time to hospital discharge, and parental satisfaction

2. How studies were identified

The following databases were searched to February 2016:

• CENTRAL (The Cochrane Library, Issue 1, 2016)
• MEDLINE
• EMBASE
• CINAHL
• ClinicalTrials.gov
• WHO International Trials Registry and Platform
• ISRCTN Registry

Reference lists of identified studies and relevant conference proceedings were also handsearched

3. Criteria for including studies in the review

3.1 Study type

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

(Crossover trials were excluded)

3.2 Study participants

Preterm infants (<37 weeks’ gestation), fed at least partially enterally with either formula milk or human breast milk

3.3 Interventions

Responsive feeding, where an enteral feed is started in response to the infant’s feeding cues and is concluded once the infant expresses satiation or when a set volume of intake is reached, was compared with scheduled interval feeding, whereby feeds are given at timetabled intervals without regard to the infant’s sleep status

(Treatment and control groups must have received the same type of milk and trials investigating type of milk as a co-intervention were excluded)

3.4 Primary outcomes

• Growth: weight gain (g/day or g/kg/day), linear growth (mm/week), skinfold thickness (mm/week), head circumference (mm/week); and proportion of infants who remain below the 10th percentile for weight, height, or head circumference at follow-up
• Duration of hospital admission
• Parental satisfaction

Secondary outcomes included time to establishment of full oral feeding, nutrient intake during the trial, duration of breastfeeding and breastfeeding rates (any and exclusive), milk aspiration, hypoglycaemia requiring treatment, feed intolerance, and neurodevelopment at >12 months’ corrected age

4. Main results

4.1 Included studies

Nine trials enrolling 593 infants were included in this review:

• Participants were all clinically stable preterm infants between 32 and 36 weeks’ postmenstrual age, enterally fed and at transition from intragastric tube feeds to oral feeds
• One trial recruited preterm infants with a history of bronchopulmonary dysplasia (defined as receipt of supplemental oxygen therapy at 28 days postnatal)
• One study enrolled infants at the start of the transition to oral feeds where infants were mainly fed by intragastric tube, whilst the other studies enrolled infants later in the transition phase when they were receiving the majority of their feeds orally. For six studies, when infants were allocated to the intervention group, their intragastric feeding tubes were removed
• Most studies defined responsive feeding as allowing the infant to feed orally in response to hunger cues, with feeding being ceased in response to satiation cues; in three studies, infants not demonstrating feeding cues within five hours were fed orally or via intragastric tube; in two trials, the infant was assessed every three hours for readiness to feed
• Scheduled interval feeding was defined as feeding either orally or via intragastric feeding tube at three to four hourly intervals to achieve a target intake of 100 to 160 mL/kg/day

4.2 Study settings

• Canada (2 trials) and the United States of America (7 trials)
• The studies were all carried out by healthcare personnel attached to neonatal units

4.3 Study settings

How the data were analysed
Responsive feeding was compared with scheduled interval feeding. Fixed effect meta-analysis was used to generate pooled relative risks (RR) for dichotomous data and mean differences (MD) for continuous data, with corresponding 95% confidence intervals (CI). To investigate potential sources of heterogeneity, the following subgroup analyses were planned:

• By breastfeeding status: exclusively breastfed
• By feeding cue assessment: infants’ responses to non-nutritive sucking being used to assess hunger
• By study type: cluster-randomized trials

Results
Responsive feeding versus scheduled interval feeding
Growth
Pooled analysis of data from four trials involving 305 infants revealed a statistically significant lower rate of weight gain in the responsive feeding group in comparison to the scheduled interval feeding group (MD -1.36 g/kg/day, 95% CI [-2.44 to -0.29], p=0.01; I²=35%). In three other trials, there was no significant difference between groups, but in these trials the intervention lasted less than one week. In one further trial, a lower weight gain was reported for the responsive feeding group, but data on the variability and statistical significance of this difference were unavailable. No data were available for other pre-specified growth outcomes.

Duration of hospital admission
Meta-analysis of two trials including 145 infants showed no difference in length of hospitalisation between treatment groups (MD -1.0 days, 95% CI [-9.4 to 7.3], p=0.81; I²=43%). Two further studies reported no significant difference between responsive and scheduled interval feeding groups in length of hospital stay, and another reported a two-day difference favouring the intervention group, although data on the variability and statistical significance of this difference were unavailable. In two trials including 138 infants, postmenstrual age at discharge was statistically significantly lower in the responsive feeding group (MD -0.48 weeks, 95% CI [-0.94 to -0.01], p=0.04; I²=47%). Two trials reported that time from enrolment to hospital discharge was shortened with responsive feeding: 2.7 days versus 8.9 days, and 7.2 days versus 8.4 days, with the former reported as being statistically significant.

Parental satisfaction
No data were available for this outcome.

Additional outcomes
Time to establishment of full oral feeds after trial entry was statistically significantly shorter with responsive feeding (MD -5.5 days, 95% CI [-6.8 to -4.3], I²=8%; 2 trials/167 participants). Volume of milk intake per day was lower in the responsive feeding group, although this difference did not reach statistical significance (MD -5.75 ml/kg/day, 95% CI [-12.12 to 0.62], I²=42%; 4 trials/208 infants). No difference in energy intake was observed between treatment groups (MD 0.52 kcal/kg/day, 95% CI [-2.33 to 3.37], I²=86%; 3 trials 208 infants), and no data were available for other secondary outcomes.

5. Additional author observations*

In general, the methodological quality of the trials was poor, with all studies being at high or unclear risk of bias due to lack of blinding, and attrition bias likely having affected results from two trials in which almost half of all participants were discharged before study completion. The findings reported here should therefore be interpreted with caution. Using GRADE criteria, the quality of the evidence for the outcomes weight change during study period (g/kg/day) and time to establishment of full oral feeds was rated as being of low quality. Trials included in this review were conducted in neonatal care centres in Canada and the United States of America among preterm infants who were clinically stable. Therefore, the findings may not be generalizable to unwell preterm infants or to low- and middle-income country settings.

Overall, the evidence reviewed here does not provide strong support in favour of responsive feeding for preterm infants as an alternative to scheduled interval feeding. The rate of weight gain was lower among infants receiving responsive feeding, and the reduction in time to transition from enteral tube to full oral feeding did not appear to affect the primary outcome of duration of hospitalisation in a consistent manner.

Future research should focus on infants at the transition period from enteral tube to oral feeding, could include assessments of resourcing issues, such as use of staff time, and could involve parent support and advocacy groups in study design to inform the selection of other relevant outcomes.