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?

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.

4 Responses to Probiotics: so what about those ELBW babies?

  1. annie janvier says:

    Keith,
    I love your blog (as I call it our forth child). I love it that you are a man of science. Probiotics are the most evidence based and studied therapy in neonatology. I am not sure more science will make people change their minds for probiotics. There is already plenty of science.
    In this case the resistance to utilization of probiotics seems more of 2 origins:
    1. A ”belief” more than anything else. It seems some people do not want to see the data and the pros and cons. Not sure what to do in this case, how to challenge irrationality, or gut feelings (jeu de mot)
    2. Or apathy in front of bureaucracy that ”does not want us to use probiotics”. I hear this most often, with many groups incriminated: hospital administration, pharmacy committee, infection control committee, anti-yogurt committee… Indeed, many neonatologists have tried, somebody said ”no” and their job is done. Here I think you could help. In my opinion, when we can save a life with minimal risk at almost no cost, ”no” is not acceptable. Try again, and try again until you get a yes. In our institution, parents helped us and demanded probiotics after we informed them. One maman has been particularily instrumental in this (Mrs Sibilev, if you read this, you are our hero and you know it; and no, confidentiality does not matter to her for those with legal minds).

    As a neonatologist and parent of an ex 24wk baby (and a ethicist, whatever that is), I find the lack of information we give to parents in this matter unethical. Parents should be informed of the data.
    If you are a parent reading this blog, demand probiotics. There are safe products that can be found at the moment in the US and Canada.
    If you are a parent, you can do what Mrs Sibilev did. Parents can buy these products as they are very cheap. And parents can bring them to the unit and demand that they are administered to their babies. And units can then scratch their heads and find whomever said no and have further discussions. And eventually get to yes.

  2. katharinastaub says:

    As a parent of 27 week twins, I would want to know the best therapies available for my children. I do think hospitals have to inform parents about what works, even more so if the therapy is cheap and effective!
    I don’t remember hearing about probiotics when we were in the hospital. (But then I don’t remember many things that were said to me during that stressful time).
    We did hear about NEC though. In my opinion NICUs have an obligation to inform families of the positive impact probiotics have on babies born very small.

  3. Alfonso Pantoja says:

    Keith:I just found this blog and let me congratulate you. I am a neonatologist in Colorado currently using exclusive BM feedings and a probiotic preparation as a way to prevent NEC.
    I just heard Roger Soll’s presentation in the VON meeting. He mentioned the PiPS study that was just finished. Apparently a trial with a single organism as a probiotic.
    He mentioned that in this large study there was no difference between the groups with a 10% incidence of NEC in the treatment and the control groups.
    Where can I findo more information about this trial?
    Is there a higher incidence of NEC in England?

    BTW, no NEC in my NICU for almost 2 years (should have had 8 cases by now)

    Alfonso Pantoja, MD

  4. N. Ambalavanan MD says:

    Just to revisit this issue – have you seen this?: http://www.cdc.gov/fungal/rhizopus-investigation.html

    Basically, all “probiotic” medications are marketed as food supplements (considered “Generally Regarded As Safe” or GRAS products by the US FDA), and not as drugs, which have to be manufactured to “Good Manufacturing Practices” (GMP). We have analyzed samples of “probiotics” before in reference labs and found that they often do not contain what they are supposed to contain and sometimes have pathogens or fungi.

    Some additional refs: Elliott and Teversham. S Afr Med J 2004; Aureli et al. Int J Food Microbiol 2010; Huys et al. Res Microbiol 2006
    To summarize these refs:
    Many do not have the advertised bacteria –
    Do not meet guidelines (87%) – either quantitative or qualitative – widespread use of misclassified bacterial species or with fictitious names
    Incorrect identification (only 3 of 9 accurate)
    Incorrect numbers (0 of 25 samples had live B.bifidum – only sporadically seen as dead cells)
    Mis-identified cultures at genus or species level at onset of production (28%): 34 cultures from 10 different companies
    Many have pathogens -Enterococcus faecium and Saccharomyces cerevisiae are common; Toxin-producing B. cereus also seen

    Development of probiotics as drugs using GMPs has been done, but is still in the RCT process…e.g.http://clinicaltrials.gov/show/NCT01954017
    I would suggest probiotics need to be manufactured as drugs, and efficacy of these drugs shown in RCTs, before their use in ELBW infants becomes widespread.

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