Responses to letters regarding our Journal of Pediatrics Probiotics article

Posted on 26 October 2014 by Keith Barrington

Here are my answers to 2 letters written regarding the article that Annie Janvier, Josianne Malo and I wrote about the impact of probiotics in our NICU.

I just realized that Elsevier’s rules allow me under the ‘permitted scholarly posting’ rules to post the text of my accepted publication (in this case my reply to the letters), as long as I don’t use the added formatting and so on of the final published article; and as long as I stretch it a bit and call this blog a website operated for scholarly purposes, also I have to include the following :

NOTICE: this is the author’s version of works that were accepted for publication in The Journal of Pediatrics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to these works since they were submitted for publication. Definitive versions were subsequently published in The Journal of Pediatrics. 2014;165(2):417-8. doi: 10.1016/j.jpeds.2014.04.037 (I will add the reference for the second letter when it becomes available).

The first reply, which appeared on-line in May and in print in August, was in response to a letter from Oncel and others, in which they refer to their own studies which did not individually show a significant reduction in the incidence of NEC. Their letter can be accessed from here, and the references to their studies are given at the end of my response.

REPLY:

The efficacy of probiotics is no longer questionable. They are more firmly established than almost any other therapy in neonatology. It is true that there remain many questions, but none of those questions can be addressed by placebo-controlled trials. With respect to the studies produced from the authors’ own unit, I would submit that the results of the studies by Sari et al (1) and Oncel et al (2) are consistent with the published data regarding the efficacy of probiotics.

The study by Sari et al (1) showed a reduction in necrotising enterocolitis (stages 2 and 3) from 10 cases to 6 cases (of 110 in each arm of the trial) that is a 40% reduction with the use of Lactobacillus sporogenes. This result is consistent with the recent meta-analysis. Although that difference is not statistically significant, the very low rate of NEC in their unit makes the power of their study inadequate. They also showed a reduction in the combined outcome of death or NEC, from 13 cases to 9 cases.

The trial by Oncel et al (2) using L reuteri showed an extremely low rate of NEC in the control infants (5 cases among 200 enrollees), and a nonsignificant reduction in both NEC (to 4 cases) and death or NEC (from 13.5% to 10%).

I would concur with the authors that it appears that Saccharomyces are ineffective. This probiotic fungus may have some effect in reducing colonization with pathogenic fungi, but for the moment, any effect on NEC seems unlikely.

When there is already substantial evidence available, a Bayesian approach to new data should be taken. Such an approach shows that the 2 trials mentioned confirm other data. Clearly, if a very low background rate of NEC occurs without probiotics, the absolute benefit of their introduction will be smaller.

The data in those 2 studies also support the other major benefit of probiotics—improved gasrointestinal function. Both studies showed reductions in feeding intolerance with probiotics. Also, both studies support the safety of lactobacillus administration. The incidence of sepsis was almost identical between the 2 groups in the study by Sari et al, and was substantially lower in the probiotic group in the study by Oncel et al.

The studies by Oncel et al and Sari et al support the safety and efficacy of probiotics. Future studies comparing different preparations, doses, timing, and duration would be optimal. However, they will have to be very large to detect any clinically important differences. Probably large cluster randomized trials, using a neonatal intensive care unit as the cluster, will be the only economically viable way of answering these remaining questions.

References

1.  F.N. Sari, E.A. Dizdar, S. Oguz, O. Erdeve, N. Uras, U. Dilmen. Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr, 65 (2011), pp. 434–439

2.  M.Y. Oncel, F.N. Sari, S. Arayici, N. Guzoglu, O. Erdeve, N. Uras, et al. Lactobacillus Reuteri for the prevention of necrotising enterocolitis in very low birthweight infants: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed, 99 (2014), pp. F110–F115

The second letter and the reply that Annie Janvier and I wrote will be published shortly, the letter accepts the scientific evidence for probiotics, but discusses, rather, concerns about safety. The authors were concerned about the regulatory status of probiotics in the USA which discourages companies from producing appropriate preparations. (I will add the appropriate links as they become available)

REPLY:

We certainly agree that it is essential when giving probiotics to preterm infants that we actually give probiotic organisms and not pathogens. Quality control of a product with well-characterized organisms and evidence that there are active probiotic organisms and no other contaminants present at the time of administration are required.

We agree with Drs Chan, Soltani and Hazlet that there is no doubt about the efficacy of probiotics for the prevention of NEC; the use of products identical to those used in the large multi-center RCTs, or other products with adequate evidence of their composition should therefore be considered mandatory. In fact there are sources of probiotics in North America that satisfy these conditions. The product (ABCDophilus) used in the Proprems trial(1) is manufactured by Solgar in New Jersey, a company with a good track record of quality control. The product which we used(2) has a Natural Product Number from Health Canada, which is evidence that the manufacturers follow GMP, that the strains are known and their DNA registered in the appropriate database, and that they are free of contamination with other organisms.

Another product used in several multicenter RCTs, Infloran, is also produced by a company with excellent quality control. The recent publication of the data from the German Neonatal Network(3) was from units that use Infloran for their infants. Infloran may be less readily available in the USA, but it certainly is available elsewhere.

There are products available in North America and elsewhere which could be used to protect preterm infants against NEC.

We agree that there is a need for a reconsideration of the regulatory status of these organisms, to enable manufacturers to supply safe, effective preparations, and to enable their use in the NICU. Many thousands of lives could be saved, and many hundreds of metres of intestine, not to mention the billions of neurones and the millions of dollars.

  1. Jacobs SE, Tobin JM, Opie GF, Donath S, Tabrizi SN, Pirotta M, et al. Probiotic effects on late-onset sepsis in very preterm infants: a randomized controlled trial. Pediatrics. 2013;132(6):1055-62.
  2. Janvier A, Malo J, Barrington KJ. Cohort study of probiotics in a north american neonatal intensive care unit. The Journal of pediatrics. 2014;164(5):980-5.
  3. Hartel C, Pagel J, Rupp J, Bendiks M, Guthmann F, Rieger-Fackeldey E, et al. Prophylactic Use of Lactobacillus acidophilus/Bifidobacterium infantis Probiotics and Outcome in Very Low Birth Weight Infants. The Journal of pediatrics. 2014(0).
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Ventilating babies during resuscitation

Posted on 15 October 2014 by Keith Barrington

Three recent-(ish) articles examining how we should ventilate babies and monitor what we are doing.

Milner A, Murthy V, Bhat P, Fox G, Campbell ME, Milner AD, et al. Evaluation of respiratory function monitoring at the resuscitation of prematurely born infants. Eur J Pediatr. 2014:1-4.

In this study, respiratory function monitoring with tidal volume, airway pressure and exhaled CO2 was routinely introduced in 2 London hospitals. The authors then asked trainees whether they found it useful, and what they thought the right tidal volume should be. As you might imagine the answers were quite variable, and integrating more than one sign, such as a lack of exhaled CO2 despite measured tidal volumes, was quite variable.

van Vonderen JJ, Hooper SB, Hummler HD, Lopriore E, Te Pas AB. Effects of a Sustained Inflation in Preterm Infants at Birth. The Journal of pediatrics. 2014.

Tony Milner was one of the authors of that previous article; many years ago he demonstrated that standard ventilation techniques led to an apparent ‘opening pressure’, where a substantial positive pressure was required to get air into the lungs, and that the end-expiratory volume of the lungs in the first few breaths remained very low. In contrast a long slow inflation (3 to 5 seconds) eliminated the opening pressure, in intubated babies, and led to establishment of an FRC. This new article used a pressure of 25 cmH2O and  duration of 10 seconds, delivered by face mask, but was unable to show the establishment of an FRC, unless the babies were breathing.

Murthy V, Creagh N, Peacock J, Fox G, Campbell M, Milner A, et al. Inflation times during resuscitation of preterm infants. Eur J Pediatr. 2012;171(5):843-6. This observational study during resuscitation, using the same respiratory function set up as in the first article, could not show that the variation in inflation times which occurred by chance during resuscitation (from 0.3 to 3 seconds) did not affect inspiratory flow duration.

Neil Finer reviews the current state of the art of prolonged inflations, his conclusion: ‘not ready for prime time’.

Schilleman K, Witlox RS, van Vonderen JJ, Roegholt E, Walther FJ, te Pas AB. Auditing documentation on delivery room management using video and physiological recordings. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014. If you video record resuscitations, and then compare the tapes to what is actually written in the patients chart, this is what you get:

The clinical condition of the infant at birth was documented in 76% and 1 min Apgar scores in 98%. Respiratory support was correctly documented in 83%, heart rate in 37% and oxygen saturation in 13%. In 57% use of supplemental oxygen and its indication were correctly reported. Seven infants were intubated and this was correctly documented in 57%. Apgar scores were compared between the recordings and the medical records. At 1 min, 5 min and 10 min after birth the Apgar score, given by the researcher using the recordings, was similar to the scores in the medical records in 33%, 44% and 53%, respectively.

Hmmm.. maybe we need cameras everywhere and make the recordings part of the patients chart… or maybe not!

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Now Cross-Posting to 99NICU.org

Posted on 15 October 2014 by Keith Barrington

Stefan Johansson, who runs the NICU website/community 99NICU.org asked if I would be interested in cross-posting my Neonatal Research posts in the blog section of their website.

I will post most of my musings over at their website as well, probably keeping the ‘not neonatology’ stuff here, and maybe some things when I am more critical.

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Appropriate outcomes for neonatal research

Posted on 14 October 2014 by Keith Barrington

Neil Marlow has published a thoughtful, and thought provoking, article to address the issue outlined in the title. What are the appropriate outcomes when designing neonatal research studies?

It has become almost a rule, that a multi-center trial of an intervention in neonatology, especially if it is planning to enroll very preterm infants, has to have ‘survival without neurological or developmental disability’ as the primary outcome, with the ‘disability’ part measured at about 2 years.

There is some value to this outcome, very preterm infants have high mortality and high morbidity in those domains, infants who die cannot be developmentally delayed, so they are competing outcomes that need to be taken into account if we are trying to construct a dichotomous end-point. Like most things in trial design we have to make compromises, later follow up might be nice, but it will increase costs and increase drop-out rate; follow up to 2 years allows good retention rates, if you work hard at getting parents to return, but means you need to use developmental screening tools which are developed for very young infants.

There are however, numerous problems with this approach, which are discussed in this piece. (Marlow N. Is survival and neurodevelopmental impairment at 2 years of age the gold standard outcome for neonatal studies? Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014).

I also think we do need to rethink this approach for some of the following reasons (which overlap with the reasoning of Neil Marlow)

1 Developmental delay is not a dichotomous outcome. It is convenient for research planning to think of children either having impairment or not, but of course, developmental delay is a continuum, arbitrarily deciding that a Bayley score of 69 is delayed, but a score of 71 is not, misses all sorts of nuances in outcomes.

2. Developmental delay is not stable over time: many children labelled as delayed at 2 years have intellectual abilities in the long term that are close to, or above, average (in fact according to the work of Maureen Hack, 2/3 of them do). The improvement in developmental scores is correlated more closely with social advantages than to anything which occurs in the neonatal period.

3. Developmental delay has little or no influence of quality of life. Children with developmental delay can, and usually do, have an excellent QoL. If the purpose of your research project is to decided which therapies we should use in the future, then whether or not the therapy affects quality of life should be our main consideration, but as far as I know, no therapy has been shown to affect quality of life, apart from effects on quantity of life. In other words, surfactant for RDS increases quality of life, because more children are alive to have a life of good quality!

4. Very few neonatal preterm studies have ever shown an effect on neurological impairment or developmental delay. Of all the studies in the very preterm baby, which have actually been confirmed to reduce developmental delay? Maybe someone should do a systematic review to answer that question, of the top of my head there is Caffeine (at least when defined by developmental screening at 2 years, but not when examined at 5 years), and then there is… well that’s about it. So many of our decisions about which treatments are proven to be beneficial are really based on their impacts on survival, or on other morbidities, such as lung injury (another non-dichotomous outcome that we ‘dichotomize’ for facilitating compound outcomes).

5. Another important consideration is that the effect of an intervention on survival and on neurological or developmental outcomes may be in different directions. Which means that a trial might be ‘negative’ but still have important results that should change practice. I don’t know if this has happened for the outcome of survival and 2 year developmental screening test scores, but it is analogous to what SUPPORT showed. SUPPORT was a negative trial. The composite primary outcome (survival without severe retinopathy) was not affected by different saturation target ranges, because the impacts on the two components of the outcome were in opposite directions.

Neil Marlow includes a discussion of the TIPP trial, which showed a reduction in severe brain injury, a reduction in serious pulmonary hemorrhage, and a reduction in need for PDA ligation. But, the study did not show an overall improvement in  developmental outcomes with indomethacin prophylaxis compared to control. I think it was an excellent trial with reliable results, but because of the lack of improvement in the primary outcome it has discouraged the use of prophylactic indomethacin. However, there was a reduction in severe hemorrhage from 13 to 9%: if the only effect of indomethacin on the brain or on development was the reduction in IVH, and if the patients who had a severe IVH had an increase in neurodevelopmental ‘impairment’; then any benefit would only have been on those 4% who escaped IVH, and the impact on the scores of the groups as a whole would have been very small. This study was therefore grossly underpowered, in the sense that it would not be able to show that a reduction in severe IVH of that magnitude had an overall effect on the developmental scores of the entire group.

In their answer to an article which questioned why prophylactic indomethacin was not more widely used, De Mauro et al stated

” TIPP failed to demonstrate any long-term benefit of indomethacin prophylaxis, but the study also failed to prove the absence of long-term harm”

Which is true, but I would say it is not the whole story, because you could equally well say, ”TIPP failed to prove the absence of long term benefit, but the study also failed to demonstrate any long-term harm ”

A study with no statistically significant overall effect on developmental outcome always means that there is some possibility that developmental outcomes are actually improved, or actually harmed, depending on the range of the confidence intervals of the result. TIPP gives some confidence that developmental outcomes are not dramatically harmed by indomethacin, but there will also be a possibility that in reality there is some impact on development: the confidence intervals of the study result gives us a range within which we can say, with 95% confidence, the true difference in the means of the Bayley scores lie. Uncertainty has been reduced by doing the trial, it means it is likely that the true impact on the Odds of an infant (similar to those eligible for the trial) having a Bayley score below 70 are between an Odds ratio of 0.8 and 1.4 if they receive prophylactic indomethacin rather than not. Or, to put it in terms that I find easier to conceptualize, the risk of having a Bayley score below 70 is probably (with 95% confidence) between a 17% reduction and 29% increase in risk, if you get prophylactic indomethacin.

If most survivors of NICU do well (as they do) and almost all have a good quality of life (which they do) and the history of neonatal intensive care research has shown it is extremely difficult to demonstrate improved developmental outcomes at 2 years (as I discuss above); and developmental outcomes at later ages than that (when testing is more relevant for functional ability) have never been affected by a neonatal intervention, then maybe we should reconsider our outcomes. I think that trials should be designed and powered to examine effects on improving survival and other serious short term complications, such as severe cerebral hemorrhage, necrotizing enterocolitis and so forth, and that surveillance for other medium and long term outcomes, including developmental screening test scores, should be considered important for ensuring safety.

I also think we should be asking parents about these things. Is a reduction in severe brain hemorrhage an outcome that they think is important, even if we can’t prove an advantage in terms of Bayley scores?

Which is all very similar to what Neil Marlow says in his article. So he must be right.

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Upcoming Webinar

Posted on 9 October 2014 by Keith Barrington

If you are on their mailing list you will have received the following notice:

Keith Barrington Oct. 22

Register today for our 2014-2015 Children’s Mercy Bioethics Center webinar series.

The focus this year is “Ethical Issues in Pediatric Clinical Research.” Our first webinar is Wednesday, Oct. 22 with Keith Barrington, MD. Dr. Barrington will discuss,

“More or Less: the Ethical Responsibilities of Clinical Researchers. ” 

Visit https://cmhbioethics.webex.com/ for registration information. 

I believe you can register for this wherever you are (I guess that’s a webinar!) and that it is without cost and without other obligations, you just need to register to get access.

I hope to be able to be stimulating and perhaps challenging.
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Probiotics prevent NEC in rats too!

Posted on 8 October 2014 by Keith Barrington

Mark Underwood has been very active in the investigations of probiotics and their effects on the neonatal bowel. His new publication is a fascinating exploration of what happens in a rat model of NEC when they receive bifidobacterium infantis, also known as bifidobacterium longum subspecies infantis. (I don’t pretend to understand how bacteriologists decide if 2 strains are the same species or subspecies, it all seems somewhat arcane to me; I sort of get Gram stains but after that…).

One of the first good things about this study is the opening line of the abstract ‘

Probiotics decrease the risk of necrotising enterocolitis

No ifs, ands, or buts; I like it.

The introduction is a brief  resumé of the lines of evidence in animal models regarding the efficacy of probiotics for prevention of NEC.

The most promising preventative approaches to date include provision of human milk and probiotics (4,5). The observations that many Enterobacteriaceae out-compete commensal organisms in the inflamed intestine by utilizing an alternative respiratory pathway (6), together with the recent descriptions of a bloom of Enterobacteriaceae associated with NEC (7) shed new light on a possible central role of the intestinal microbiota in this disease.

The neonatal rat model of NEC is an invaluable experimental tool for examining the pathogenesis of NEC and potential mechanisms of protection (8,9,10). The strength of this model is its inclusion of stressors and enteral feeding, both of which are factors associated with human NEC. In the rat model, the stressors include separation from the dam, tube feeding, hypoxia, hypothermia, and enteral nourishment with bovine-based rat milk substitute (11).

Previous studies with this model have demonstrated a protective effect of probiotic Bifidobacterium bifidum with decreased NEC, decreased apoptosis, and decreased inflammation (8,9,10). Mouse and piglet studies have demonstrated alterations of the intestinal microbiota in NEC (12,13)

The references are all listed at the end of this post for those interested.

These investigators studied 3 groups of neonatal rats. They either got donor breast milk (that is they were fed by surrogate rat mummies) or they received artificial formula, or they received artificial formula and probiotics. The animals in the 3 groups were exposed to asphyxia and cold stress, 1 minute of breathing 100% nitrogen and 10 minutes of being put in the fridge (at 4 degrees). None of the breast-milk fed baby ratlings developed NEC, but 80% of the formula fed ones did. Giving B. infantis decreased this to about 36%. There was a decreased expression of a number of pro-inflammatory mediators in their intestines and less histologic injury also. Interestingly they weren’t able to find a lot of bifidobacteria in the caecum of the animals, or to note any consistent difference in the microbiomes between those which got bifidos and those which did not.

Apart from the demonstration of gut protection and NEC prevention and reduced inflammation with probiotics, this study also illustrates what we don’t yet understand about probiotics. In our work, which we haven’t yet finished analyzing to publish, in preterm babies who all received probiotics, only a tiny proportion of fecal organisms were the probiotics. Nevertheless they have clinical effects. Work like this new study will help us to understand, and eventually to select the most promising organisms for future clinical trials.

4. Underwood MA. Human milk for the premature infant. Pediatr Clin North Am2013;60:189–207.

5. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics 2010;125:921–30.

6. Winter SE, Winter MG, Xavier MN, et al. Host-derived nitrate boosts growth of E. coli in the inflamed gut. Science 2013;339:708–11.

7. Mai V, Young CM, Ukhanova M, et al. Fecal microbiota in premature infants prior to necrotizing enterocolitis. PLoS One 2011;6:e20647.

8. Khailova L, Dvorak K, Arganbright KM, et al. Bifidobacterium bifidum improves intestinal integrity in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol2009;297:G940–9.

9. Khailova L, Mount Patrick SK, Arganbright KM, Halpern MD, Kinouchi T, Dvorak B. Bifidobacterium bifidum reduces apoptosis in the intestinal epithelium in necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2010;299:G1118–27.

10. Underwood MA, Kananurak A, Coursodon CF, et al. Bifidobacterium bifidum in a rat model of necrotizing enterocolitis: antimicrobial peptide and protein responses. Pediatr Res2012;71:546–51.

11. Dvorak K, Coursodon-Boyiddle CF, Snarrenberg CL, Kananurak A, Underwood MA, Dvorak B. Helicobacter hepaticus increases intestinal injury in a rat model of necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 2013;305:G585–92.

12. Carlisle EM, Poroyko V, Caplan MS, Alverdy JA, Liu D. Gram negative bacteria are associated with the early stages of necrotizing enterocolitis. PLoS One 2011;6:e18084.

13. Azcarate-Peril MA, Foster DM, Cadenas MB, et al. Acute necrotizing enterocolitis of preterm piglets is characterized by dysbiosis of ileal mucosa-associated bacteria. Gut Microbes 2011;2:234–43.

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The voice of Parents, now in print.

Posted on 8 October 2014 by Keith Barrington

Katharina Staub and other parents have written and published an article in Acta Paediatrica. ‘ Our child is not just a gestational age‘.

In the NICU babies are often referred to by how many weeks they spent in the uterus, so X is a 24 weeker, Y is a 23 weeker, etc. Worse, decisions are made about whether or not to institute or continue life sustaining interventions based on estimates of completed weeks of gestational age, when other factors are just as important, and babies may not even be offered active intervention as a result of a sometimes very limited analysis; which gives an overwhelming influence to the estimated (or often, guesstimated) gestational age.

I have already discussed this article in a post, as it was already available on-line, but as it has now appeared in the print edition I thought I would give another mention to this article, one of too few which have really given a voice to parents.

Posted in Neonatal Research, The CPS antenatal counselling statement | Tagged | 1 Comment

Can Paracetamol (acetaminophen) close the ductus arteriosus?

Posted on 29 September 2014 by Keith Barrington

A new publication by Afif El-Khuffash and his colleagues (El-Khuffash A et al. Efficacy of paracetamol on patent ductus arteriosus closure may be dose dependent: evidence from human and murine studies. Pediatr Res. 2014;76(3):238-44) describes a retrospective review of paracetamol use in newborn infants, and an in vitro study using mouse ductal tissue. The clinical part of the paper shows that with a short course of oral paracetamol there was no response, with a longer course of oral paracetamol there were some responses, and with intravenous paracetamol for between 2 and 6 days there were many PDA closures, and others that tended to constrict. The numbers are very small but suggestive.

Afif also reports the effects of paracetamol and indomethacin on preterm and term mouse ductal tissue. Paracetamol had no effect on the preterm, and lesser effect on the term, compared to indomethacin. With high enough concentrations of paracetamol there were indeed constrictive responses to paracetamol.

This all suggests that it is indeed possible that paracetamol might be effective. But I won’t be expecting miraculous results.

This is also the suggestion of an article from Israel (Nadir E, Kassem E, Foldi S, Hochberg A, Feldman M. Paracetamol treatment of patent ductus arteriosus in preterm infants. J Perinatol. 2014;34(10):748-9), 7 extremely preterm infants with large PDA were treated, they either had failed ibuprofen or had a contra-indication. Most closed without surgery. Again suggestive but no more than that.

Presumably there are placebo controlled trials coming, I hope so.

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Probiotics: so what about those ELBW babies?

Posted on 24 September 2014 by Keith Barrington

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

Posted on 23 September 2014 by Keith Barrington

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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