Does the way we feed babies affect Necrotizing Enterocolitis?

There is a widespread feeling that the method of introduction and advancement of feeds affects the frequency of necrotizing enterocolitis (known as NEC). Multiple observational studies have been published that seem to support this fear. However when we search for randomized controlled trials comparing feeding practices it is almost impossible to find any support for this idea.

One example is a nice new multicenter RCT called the ADEPT trial (Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Linsell L, Juszczak E, Brocklehurst P, Abnormal Doppler Enteral Prescription Trial Collaborative G: Early or delayed enteral feeding for preterm growth-restricted infants: A randomized trial. Pediatrics 2012, 129(5):e1260-1268. This trial was enrolled 402 preterm infants with an increased risk of NEC. The risk was increased because they were growth restricted, and had abnormal antenatal dopplers. The increase in risk was born out in the results; the threshold gestational age for eligibility was 35 weeks, and the actual mean gestational age was about 31 weeks in each group, so you would suppose normally that the risk was lower than for say a group of babies of 28 weeks gestation, yet there was a 18% rate of NEC in one group and 15% in the other. If we just examine the stage 2 and 3 NEC, ie those often referred to as ‘definite’ NEC, there were 17 in the early feeding group and 18 in the late feeding group. The difference in feeding practices was as follows, the early feeding group were started on feeds at 24 to 48 hours, the late group had 5 days of not being fed, and started at 120 to 144 hours. Apart from the delay, the feeding protocol was then the same in both groups.

Obviously if you delay feeds the babies are liable to reach full feeds later, which was shown, the babies are also likely to have more prolonged IV feeding, and more complications of IV feeding, including cholestasis and secondary infections. All of these were shown, but the increase in infections was not statistically significant.

So the delay in introducing feeds only caused morbidity, with no benefit.

How about other studies of a similar intervention? Another much smaller study of infants with abnormal dopplers and delayed feeding, (Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T, Chatziioannidis E, Kyriakidou M, Nikolaidis N: Early versus delayed minimal enteral feeding and risk for necrotizing enterocolitis in preterm growth-restricted infants with abnormal antenatal doppler results Amer J Perinatol 2010, 27:367-373. randomized 80 babies to start feeds either at < 6 days or at 6 days or more. The early group started on average on day 2 the late group on day 7. This was, as acknowledged by the authors an under-powered pilot study, nevertheless they showed no benefit.

A Cochrane review of 5 trials comparing early to delayed introduction of feeds in the preterm, including these 2 (the others did not select by the presence of growth restriction, but by birth weight alone), also found no evidence of benefit of delaying the introduction of feeds. (reference 1 below)

How about the rate of advancement of feeds? There are 4 trials that have compared advancing feeds at a goal of 20 mL/kg/d or less to a more rapid 30 mL/kg/d or more, also reviewed in a Cochrane review. No evidence of a benefit of slow advancement was found. These rapid versus slow trials were all in babies who were fed within the first 5 days of birth, and the total number of babies randomized is about 500. (Reference 2 below)

It is interesting that in the ADEPT trial mentioned above, by Alison Leaf and her colleagues, they used a feeding advancement regime that was slower than even the slow feeding protocol in those previous RCTs, that is after starting feeds they had a goal to advance feeds by about 11 mL/kg/d in the smallest babies less than 600 g birth weight, becoming more rapid with the larger babies up to a maximum of about 15 mL/kg/d in the babies over  1250 g.

Finally what about ‘trophic’ feeds. Should we start with trophic feeding of a small volume for a while before we start to progress the feeds? Given how widespread this practice is, it is remarkable how weak the evidence base for any benefit is. Most of the trials of trophic feeding have compared trophic feeds to remaining nil by mouth; the Cochrane review of 9 trials involving over 750 infants really doesn’t show any benefit, neither in age of achieving full feeds, nor in any clinically important outcomes, including NEC. (Reference 3 below)

I think the only trial which has ever shown a possible effect of a feeding protocol on NEC is a trial by Carol Berseth, published in 2003 . That study randomized infants, when they were due to start feeds, to either trophic feeding or immediate advancement of feeds, by 20 mL/kg/day. The study was designed to enter 250 infants but was stopped early (after 144 babies) as there were 7 cases of NEC in the immediate advancement group and 1 case in the trophic feeding group. Stopping studies early is always a potential problem, especially in an unblinded study, where the outcome is based on interpretation of a clinical state and an abdominal x-ray. Of note in that study the average age of starting feeds was over 9 days in each group. My interpretation of this is that if you keep babies nil by mouth for too long, you might possibly need to feed them more slowly when you start.

So overall then, there is little or no evidence to support keeping very preterm babies fasting during the first couple of days of life, even if they are growth restricted and had abnormal antenatal doppler studies. When you start feeds there is little evidence to support trophic feeds, and little evidence to support immediate advancement of feeds either, but when you start to advance it doesn’t seem to matter how fast you advance. This really is one clinical neonatal problem that has far more opinion than data, but in general there is no good evidence that how we feed babies has any influence on NEC. It is probably much more related to whether we give breast milk, what organisms we get colonized with, the avoidance of prolonged antibiotic courses and broad spectrum antibiotics, and avoidance of gastric acid reduction.
1: Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral
feeds to prevent necrotising enterocolitis in very low birth weight infants.
Cochrane Database Syst Rev. 2011 Mar 16;(3):CD001970.

2: Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to
prevent necrotising enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev. 2011 Mar 16;(3):CD001241.

3: Bombell S, McGuire W. Early trophic feeding for very low birth weight infants.
Cochrane Database Syst Rev. 2009 Jul 8;(3):CD000504.


About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , , , . Bookmark the permalink.

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