Probiotics: so what about those ELBW babies?

After a comment to my previous post about probiotics, I wanted to clarify what I said about the ELBW baby, that is, the newborn with a birth weight below 1001 grams.

It is true that there are few studies that have reported outcomes separately under 1kg, I referred to the 3 articles quoted by the authors of the commentary. In fact one other article reported a study which was exclusively in ELBW, that is Al-Hosni et al. They had 50 patients per group and 2 cases of NEC per group.

So the data for babies who are known to be less than 1 kg looks like this


However, in many of the other studies there were large proportions of the babies who were under 1 kg.

Study Entry Criteria (birth weight, g) Mean birth weight of probiotic group
Bin-Nun <1500 1152
Braga 750-1500 1194
Dani <1500 (or <33wk) 1325
Fernandez-Carrocera <1500 1090
Kitajima <1500 1026
Lin 2005 <1500 1104
Lin 2008 <1500 1029
Manzoni <1500 1212
Mihatsch <1500 (and <30wk) 856
Rougé <1500 (and <32 wk) 1115
Samanta <1500 ( and <32 wk) 1172
Sari <1500 (or <33 wk) 1231

Some of the other studies have included larger or more mature babies, Costalos for example excluded babies under 28 weeks, and Stratiki babies under 27 weeks. Ren excluded infants under 1 kg, and two other Chinese studies that I don’t have access to the original manuscript (Di and Ke) included babies under 32 weeks.

If we redo the meta-analysis with only those studies that were restricted to the very low birth weight, (excluding even Dani and Sari above) there are over 3,600 babies in the trials, all under 1500 grams, with an average birth weight below 1200 grams in all of the studies.

In other words there are substantial numbers of babies under 1001 grams in these studies, probably around a third of them, with probably, given the birth weight distribution of NEC, at least half of the cases of NEC. (In the CNN database over the last few years about 60 to 66% of NEC cases among the VLBW babies were among those who were under 1001g)

Here is the Forest Plot:

As you can see the effect on NEC is significant p<0.00001, with little heterogeneity, and a relative risk of 0.45.

And the Funnel plot of the same data:

Is there any other therapy in the NICU where we demand separate evidence for the ELBW when it is clearly proven to be effective in the VLBW (which includes a large number of ELBWs)?

I can’t think of any, nor of any other therapy tested in RCTs which only enrolled VLBW infants and which have included 3,600 VLBW babies.

The demand for specific studies in ELBW babies is bogus. Babies over 1 kg get NEC also, so why would anyone exclude them from trials of NEC prophylaxis?

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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.

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Not neonatology, not directly at least

I am a constant follower of the Science-based medicine blogs.  They have several excellent writers including Mark Crislip who coined a widely quoted phrase about so-called integrative medicine, where science based medicine is mixed with all sorts of woo; acupuncture, homeopathy and the like. The phrase goes like this: ‘if you mix cow pie with apple pie, it does not make the cow pie taste better; it makes the apple pie worse’.

His latest post is great, discussing why otherwise rational doctors can be so seriously misled when it comes to evaluating the effects of ineffective therapies such as those mentioned above.

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Buenos Aires

On my way home from a great, but too short, trip to Buenos Aires. Spoke at a conference there. I had an afternoon off and was able to take a long walking tour, including taking the Avenida de Mayo. Where I took this picture of one view from the Plaza de Mayo, where there are many political demonstrations, including an on-going display by the veterans of the Malvinas War It shows some examples of the varied architecture of the city. See if you can tell what time it was when I took the photo.



If you can see in high enough resolution, you will note that all 3 clocks have different times (and none of them were even close!)

Thanks to Gonzalo and a great group of friends and colleagues for organizing an excellent conference. See you all again soon.

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Probiotics; why not? Too cheap, too easy?

A nice new commentary piece in the Canadian Paediatric Journal (currently behind a paywall, should be free access in 6 months, if you want a copy I am sure that a judicious request could obtain one) asks exactly that question. Richard Taylor from Victoria BC writes that maybe probiotics are not high-tech enough, not ‘sexy’ enough, not expensive enough to attract our attention. But makes the strong case that it is time that we did, time that we advocate for our babies and not wait for the sometimes turgid processes of committees and official approval before doing what we know is right.

His center has been using probiotics with excellent results, we all should be following that lead.

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Dying Later

Several people have noted that the enormous gains in neonatal survival between the 60’s and the 90’s have levelled off. A new publication from our group (not me this time, but Amélie, Rosalie, and Annie, and no, all french-canadian women do not have names that end in -ie) has examined changes in timing of death among babies in our NICU. They show that although the overall mortality, when adjusted for gestation, is unchanged over this period, the average age of death has doubled, from about 11 days to about 21.

So we have got better at preventing early deaths from respiratory failure and metabolic disturbance, but the babies remain at high risk of dying from NEC, sepsis and progressive lung failure.

This may be worse for families, as the initial hope is dashed by serious complications, or it may be better, as parents know that we tried really hard to save their baby; but impacts on families of different pathways to death have not been well studied in the NICU.

I don’t know, but my ‘gut’ feeling is that this makes things harder for families, so we need to work ever harder at ways to reduce sepsis, reduce NEC, and protect the lungs, so the early ‘saves’ become long term survivors.

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Does massage help preterm infants?

I think the answer to the question posed in the title of the post is the usual answer: ‘it depends‘. In this case it depends on what you mean by massage, and what you mean by ‘help’. All massage is not the same, so exactly how it is done, how long for, and how frequently it is done, are bound to affect the results.

A systematic review published last year Wang, L., et al. (2013). “The Efficacy of Massage on Preterm Infants: A Meta-Analysis.” Am J Perinatol concluded that there seems to be an increase in weight gain in infants receiving regular massage, and some reduction in hospital stay (likely linked to the increased weight gain), but little evidence of other beneficial outcomes.

A new trial examined similar outcomes:  Abdallah B, Badr LK, Hawwari M. The efficacy of massage on short and long term outcomes in preterm infants. Infant Behavior and Development. 2013;36(4):662-9. that is; weight gain, hospital stay and development at 12 months corrected.

This study unfortunately used two sequential prospective cohorts rather than randomizing the infants, although the outcome assessments were said to be masked, I must say that is irrelevant. In fact, in general terms I would say that there really is no point trying to mask the intervention in a study design like this, you are just fooling yourself if you think it makes a difference. The Bayley scales of infant development were administered at 12 months of age, by one of the principal investigators, who must have known that this was a sequential group study, but is described as being blind to group assignment! The Bayley scores in the first group had a mean of 106, and in the second group were an amazing 120. Which is a spectacular result from 10 episodes of massage, each of which lasted 10 minutes.

On the other hand, we can maybe give the authors, in Beirut, a bit of slack (if I was a neonatologist in Beirut right now, I am not sure I would be trying to do clinical trials!). They listed 5 outcomes as important in the publication (and don’t choose a single primary outcome); including weight gain and developmental scores: they also examined pain scores after a heel-prick, which were lower in the massage group than the non-massage group.

Overall I think that the evidence that regular massage leads to increased weight gain is reasonably good, I presume that the mechanoreceptor stimulation probably leads to an increase in bone formation by a mechanism similar to the improved bone-mineralisation that occurs with weight bearing exercise, at least that is my guess.

Any effect on other outcomes remains unproven, despite this new, potentially biased study.

I also think it is a good way to get parents involved in the care of their infants, doing something which is pleasant for the parents and for their babies, which is harmless and may well have benefits.

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