Summary of main results

The currently available trial data do not suggest that advancing enteral feed volumes at slow rates (typically 15 ml/kg/day to 20 ml/kg/day) compared to faster rates (30 ml/kg/day to 35 ml/kg/day) reduces the risk of NEC in very preterm or VLBW infants. The boundaries of the 95% CI for the estimate of effect are consistent with either four extra or four fewer cases of NEC in every 100 infants who have slow rates of feed advancement. Similarly, a meta‐analysis of data from these trials does not indicate an effect on all‐cause mortality, with the 95% CI boundaries being consistent with either nine extra or one fewer death in every 100 infants who have slow rates of feed advancement. A pre‐specified subgroup analysis showed a borderline statistically significant increase in risk of death with slow feeding in infants with growth restriction or antenatal absent end‐diastolic flow velocities. However, given that this finding was based on data from only two small trials with a total of 83 participants, it should be interpreted cautiously.

Infants who had slow advancement of feed volumes regained their birth weight several days later than infants who had faster rates of advancement of feed volumes. The clinical importance of this effect is unclear as long‐term growth or developmental outcomes have not been assessed. Similarly, infants who had slow advancement of feed volumes established full enteral feeding one to five days later than infants who had faster rates of advancement of feed volumes. Whether this is associated with such important adverse clinical consequences as a higher rate of nosocomial infection secondary to prolonged use of parenteral nutrition is not yet known, as few studies have reported this outcome. Despite the effect on the establishment of enteral feeding, the included trials did not find consistent evidence of an important effect on the duration of hospital admission.

Overall completeness and applicability of evidence

These findings should be applied with caution for several reasons. Few of the trial participants were ELBW or extremely preterm infants. One‐third of the participants in Karagol 2012 were of ELBW, but only a minority of infants in the two larger trials weighed less than 1000 g or were less than 28 weeks gestation at birth, or had evidence of intrauterine growth restriction (Rayyis 1999; Caple 2004). Infants who had severe respiratory distress requiring oxygen supplementation or ventilatory support were not eligible to participate in three of the trials (Salhotra 2004; Krishnamurthy 2010; Karagol 2012). The findings may not be applicable to these populations, which are at highest risk of developing feed intolerance or NEC (Luig 2005).

Fewer than half of all of the participating infants were fed with breast milk. Evidence exists that artificial‐formula feeding increases the risk of feed intolerance and NEC (Quigley 2014). The risk‐benefit balance of enteral feeding strategies may differ between human milk‐fed and formula‐fed very preterm or VLBW infants. It is also unclear whether the findings can be applied to infants who receive continuous infusion of intragastric feeds, as all of the infants in the included trials received enteral feeds as interval boluses. Randomised controlled trials have reported conflicting findings about the effect of continuous enteral infusion on feed tolerance in very preterm or VLBW infants (Premji 2011).

Although the finding that slow enteral feed volume advancement delays the establishment of full enteral feeds may seem intuitive, it is also plausible that advancing feed volumes faster could have resulted in more feed intolerance and therefore a delay in the establishment of full enteral feeding. The included trials pre‐specified definitions of feed intolerance that mandated interrupting or ceasing feed volume advancement, principally the detection of 'gastric residuals' (the gastric content aspirated prior to a planned gastric tube feed) and abdominal distension. However, the trial reports presented only limited data on the frequency of these outcomes. Furthermore, there is only limited evidence that the volume or colour of gastric residuals is predictive of the risk of NEC for infants whose feed volumes are advanced conservatively (Mihatsch 2002; Cobb 2004; Bertino 2009). Similarly, the clinical importance of abdominal distension or bowel loops visible through the abdominal wall (without other features of intra‐abdominal pathology) is unclear, especially in the modern era, when early and prolonged use of continuous positive airway pressure results in intestinal gaseous distension.

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 caregivers and clinical assessors to the nature of the intervention (Figure 5). Although the lack of blinding may have resulted in surveillance and ascertainment biases, it is more likely to have caused an overestimation of the incidence of feed intolerance and NEC in infants whose feed volumes were advanced faster. The assessment of abdominal radiographs for signs of NEC was masked in most trials to ensure that the diagnosis of severe 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 overascertainment of NEC in the infants who had faster rates of feed volume advancement (Tyson 2007).

Figure 5

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

Agreements and disagreements with other studies or reviews

This review focused specifically on the comparison of slow versus faster rates of feed volume advancement and did not compare progressive advancement with enteral fasting or trophic feeding (minimal enteral nutrition). Only one randomised controlled trial has compared trophic feeding with progressive enteral feed volume advancement (at daily increments of 20 ml/kg) (Berseth 2003). Although the trial found the risk of NEC to be statistically significantly higher in the infants whose feed volumes were progressively advanced, this finding should be interpreted cautiously. The trial was stopped early following an interim analysis, therefore the finding of an effect on the incidence of NEC may be spurious (Montori 2005). Caregivers and assessors were not blind to the intervention. As discussed above, this may have resulted in several sources of bias that are likely to cause an overestimation of the incidence of NEC in infants whose feed volumes are being advanced.