The Time for a Confirmative Necrotizing Enterocolitis Probiotics Prevention Trial in the Extremely Low Birth Weight Infant in North America Is Well Past

What on earth are these people waiting for?

A number of authors from Toronto and elsewhere have written a ridiculous editorial (entitled ‘The Time for a Confirmative Necrotizing Enterocolitis Probiotics Prevention Trial in the Extremely Low Birth Weight Infant in North America Is Now!’) which basically suggests that North American babies should be randomized to placebo in a trial to prove that North american babies have the same decrease in NEC as babies in the rest of the world. It recommends, in essence, that we should lie to parents about the proven benefits and safety of probiotics in order to do a North American trial, because, I guess Canadian and US babies are somehow different, even though they die of NEC just like everyone else.

Lets dissect their arguments.

1. Breast milk is proven to prevent NEC

2. Probiotics have not been adequately studied in ELBW babies (weights under 1 kg).

3. Previous studies have methodologic limitations

1. If we apply the same criteria to donor breast milk as they do to probiotics, this statement is evidently false. There are 3 informative studies in the systematic review by Bill McGuire that they quote, (the 4th study had no cases of NEC). One of them, Steve Gross’s study from 1983 excluded infants under 27 weeks, and excluded growth retarded infants, it was a single center study with about 20 patients in each of 3 groups, and there is no pre-specified sample size in the publication. Tyson’s single center, un-blinded, study, only randomized infants at 10 days of age if they were stable and extubated, they included 81 VLBW babies and had 3 cases of NEC (all in formula fed babies). Alan Lucas randomized 159 babies in a multicenter trial (initially reported in 1984 with the NEC results reported in 1990) , there was a non-significant reduction in NEC with donor breast milk compared to preterm enriched formula. Only 20 of the babies had a birth weight below 1200 grams, and there is no explicit calculation of sample size reported.

Even if we were to accept that a systematic review of 3 small trials from over 30 years ago can give us reliable information about the efficacy of an intervention among our current babies, and even if we are to ignore the potential inflation of significance when a few small trials are meta-analyzed, and if we ignore the fact that these trials have more deficiencies than the trials of probiotics; we still end up with a reduction of NEC which is barely significant, the upper limit of the 95% CI is 0.99.

This brief review shows that the data supporting the idea that donor pasteurized breast milk is preferable to preterm formula for the prevention of NEC are quite limited, of relatively low quality, from a tiny number of trials enrolling even tinier numbers of ELBW infants.  There is far better data from recent high quality trials that probiotics are effective and safe: the message of this published commentary should have been that the time is ripe for an RCT of banked human milk in ELBW babies.

2. They state that probiotics have not been shown to work in the ELBW. This is another mis-statement: In Proprems there were 14 cases of NEC among 239 controls and 10 cases among 235 probiotic treated infants. In Lin’s study there were 7 cases among 78 controls, and 4 cases among 102 probiotic receiving infants. So in both studies there was less NEC among the ELBW infants. Rougé’s small study only had 3 cases of NEC in total, so not likely to be different in the under 1 kg subgroup, and in fact they don’t report NEC under 1 kg, as opposed to over. The other studies have not reported clearly the outcomes among babies under 1 kg. Which does not mean that probiotics have not been shown to work under 1 kg. Any more than the lack of reporting by hair colour means that they don’t work in redheads. One reasonable response to this situation, if you really wanted to, would be an Individual Patient Data Meta-analysis to examine efficacy under 1 kg.

But why would probiotics work in infants over 1kg and not under 1 kg? Even if there were some reason for believing that to be the case, surely that would mean that it is now essential to give probiotics to babies over 1kg?

3. Studies have methodologic limitations? well yes, some of them do, but the major limitation that Mihatsch note in their systematic review, the source of this criticism, is that they did not report how they arrived at the sample size. Neither do the Breast Milk Banking studies that they endorse, nor many other studies reported without the CONSORT guidelines.

I hope that the authors are consistent about their desire to have more evidence, and only high quality evidence. With standards like the ones they suggest they should stop using antenatal steroids, never intubate a baby, and never use inotropes or give fluid boluses.

They end this with the following:

We argue, therefore, that now is the time to conduct in the North American setting, a high quality confirmative NEC prevention trial using probiotics in at-risk ELBW infants. Evidence arising from such a trial will provide neonatologists based in the US and Canada with new evidence that has high potential for changing clinical practice and improving the health outcomes for the vulnerable, extremely premature newborn. Equally important and a prerequisite for the introduction of probiotics in NICUs in North America is a quality-based formulation of product from reliable and dependable sources in the private sector.

I argue, therefore, that this is drivel. Neonatologists based in the US and Canada already have plenty of evidence to change practice, even if some of it comes from weird places like Taiwan, Israel, Italy, Australia and New Zealand. Babies in North American NICUs are dying and losing their bowel, and developing associated neuro-developmental impairment, because of a partially preventable condition. The Australian trial used a product which comes from New Jersey. Parents have the right to know the data and to make their own choices.

About keithbarrington

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.

3 Responses to The Time for a Confirmative Necrotizing Enterocolitis Probiotics Prevention Trial in the Extremely Low Birth Weight Infant in North America Is Well Past

  1. Stefan Johansson says:

    Thanks for a thoughtful and passionate blogg post!

    I really want to introduce probiotics in a larger NICU in Stockholm but have met some resistance … and doubt regarding <1000 g infants. As I interpret tthe latest Cochrane review (Table-material) the non-believers find some fuel: as it seems that the probiotic effect on NEC reduction is greater in the <1500 g subgroup but when restricting to <1000 g the effect is less evident.
    http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD005496.pub4/tables

    I suppose this is due to the strong independent effect of gestational week on risk of NEC, that probably mask a possible effect of probiotics. But, given the large overall effect I see no point in more trials, especially since it seems like a safe therapy.

    I struggle on and have also argued like you: if we would impose similarly high levels of evidence we would hardly allow ourselves to do anything in our NICUs.

    • I actually think there is more to this discussion than is suggested by the Cochrane review. The review authors only talk about Al-Hosni’s study, and the PROPREMS ELBW stratum to come up with their results. There are many more ELBW babies in the studies than that!
      In fact, I think I’ll write a whole post about this issue, thanks for making me think some more about it.

  2. Pingback: Probiotics: so what about those ELBW babies? | Neonatal Research

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