Summary of main results

Available trial data do not provide evidence that advancing enteral feed volumes at slow rates (15 to 20 mL/kg/d) compared with faster rates (30 to 40 mL/kg/d) reduces the risk of necrotising enterocolitis (NEC) in very low birth weight (VLBW) infants. The boundaries of the 95% confidence interval (CI) for the estimate of effect are consistent with either two extra or one fewer cases of NEC in every 100 infants who have slow rates of feed advancement. Meta‐analysis of data from these trials did not show an effect on all‐cause mortality, and prespecified subgroup analyses revealed no statistically significant effects on risk of NEC or death among extremely low birth weight (ELBW) or extremely preterm infants, nor among infants with growth restriction or evidence of absent or reversed end‐diastolic flow velocity (AREDFV). Meta‐analysis of data from eight trials showed borderline higher risk of late‐onset infection among infants who had slow advancement of enteral feeds. The point estimate suggested that an extra episode of late‐onset infection occurs for every 33 infants who have slow feed advancement.

Infants who had slow advancement of feed volumes established full enteral feeding and regained birth weight several days later than infants who had faster rates of advancement of feed volumes. The clinical importance of these effects is unclear, as longer‐term growth or developmental outcomes were not assessed. The included trials did not show consistent evidence of an important effect on duration of hospital admission.

Overall completeness and applicability of evidence

Most participants in the included trials were stable very preterm or VLBW infants of birth weight appropriate for gestational age. About one‐third of all participants were extremely preterm or ELBW, and about one‐fifth were small for gestational age, growth‐restricted, or compromised in utero, as indicated by AREDFV in the foetal umbilical artery. Infants who had severe respiratory distress requiring oxygen supplementation or ventilatory support were eligible to participate in all but three of the trials (Karagol 2013; Krishnamurthy 2010; Salhotra 2004). Therefore, review findings should be applicable across these populations at highest risk of developing feed intolerance or NEC (Luig 2005).

Most participating infants were fed, at least partially, with breast milk. Evidence indicates that artificial formula feeding increases risks 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, but available data were insufficient to show effects of different rates of feed advancement on important outcomes for infants fed exclusively with artificial formula. It is also unclear whether review findings can be applied to infants who receive continuous infusion of intragastric feeds, as a vast majority of the infants in 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 establishment of full enteral feeds may seem intuitive, it is plausible that advancing feed volumes faster could have resulted in more feed intolerance and therefore a delay in establishment of full enteral feeding. Included trials prespecified definitions of feed intolerance that mandated interrupting or ceasing feed volume advancement, principally detection of prefeed 'gastric residuals' (gastric content aspirated before a planned gastric tube feed) and abdominal distension. However, trial reports presented only limited data on the frequency of these outcomes. Furthermore, limited evidence suggests that the volume or colour of gastric residuals is predictive of risk of NEC for infants whose feed volumes are advanced conservatively (Cobb 2004; Bertino 2009; Mihatsch 2002). 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 GRADE quality of evidence for primary outcomes was "moderate", downgraded from "high" because of lack of blinding in the included trials (summary of findings Table for the main comparison). Although these trials were generally of good methodological quality, 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 2). Lack of blinding may have resulted in surveillance and ascertainment biases. It is more likely, however, to have caused an overestimation of the incidence of feed intolerance and NEC among infants whose feed volumes were advanced faster. Assessment of abdominal radiographs for signs of NEC was masked in most trials to ensure that the diagnosis of severe NEC (confirmed by radiological detection of gas in the bowel wall or portal tract) was not prone to bias. However, as 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 over‐ascertainment of NEC among infants who had faster rates of feed volume advancement (Tyson 2007).

Potential biases in the review process

The main concern with the review process is the possibility that findings are subject to publication and other reporting biases. We attempted to minimise this threat by screening the reference lists of included trials and related reviews and searching the proceedings of major international perinatal conferences to identify trial reports that are not (yet) published in full form in academic journals. Only one of the meta‐analyses that we performed included sufficient trials to explore symmetry of funnel plots as a means of identifying possible publication or small study bias, and this did not show sufficient asymmetry to raise concerns (Figure 3).

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 this trial found the risk of NEC to be statistically significantly higher among 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 blinded 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 among infants whose feed volumes are being advanced.