Reassuring Prophylactic Indomethacin Data

One of Annie Janvier’s first research projects was a case control study of the influence of prophylactic indomethacin on intestinal perforations. Under my supervision she analyzed cases of spontaneous intestinal perforation (SIP), and we analyzed the influence of prophylactic indomethacin, which was highly significantly related.

As we knew at the time, there are numerous biases in this type of research. For one, we decided to do the study because we had just had a run of SIP; often such studies are stimulated by just this kind of phenomenon. Which immediately introduces bias: what you should probably do, if you have a cluster of adverse outcomes, is to take your suspicions and analyze data from a completely independent data set, of which you are not a part. But few of us have access to such data.

We had recently introduced indomethacin prophylaxis, and had this run of SIP, so the analysis did show an associations between the 2, which made us worry, but we certainly weren’t convinced that the association was causal, nor that our data were free of bias.

As an aside, Annie, a fellow at the time, was really pissed off when a well known senior researcher, who shall remain nameless, walked past her poster and sniggered. Don’t do that folks (most of my good friends and colleagues wouldn’t dream of it): even if there are flaws in the research, we should encourage junior people to be thoughtful, to try and analyze their experiences and find ways to ask and answer questions.

That is a long introduction to a new publication from the NICHD database.

And another beef, is it really necessary, when someone does an analysis of the NICHD database, that there are 19 authors?  Did all 19 have a substantial intellectual contribution to this work? Or is it more of a little present thrown to the waiting hordes, a sort of quid pro quo, you scratch my data, I’ll scratch your CV?

Just asking.

Kelleher J, et al, et al, et al. Prophylactic Indomethacin and Intestinal Perforation in Extremely Low Birth Weight Infants. Pediatrics. 2014. This prospective cohort comparison used the generic database to examine the incidence of SIP in babies who received prophylactic indomethacin or  not, and subdivided each group as to whether they had early feeding or not. Early feeding was defined as receiving any feeds in the first 3 days of life. My European readers might laugh at that as a definition of early feeding, but there were plenty of these babies, 400 to 1000 g birth weight, who were npo for at least 3 days, indeed there were 11,000 of the 15,000 who got no enteral feeding during the first 3 days (between 1999 and 2010).

As for the results, there was no evidence that prophylactic indomethacin increased SIP, and early feeding is associated with a lower rate (there may be some confounding here, as babies who have abdominal signs and maybe early signs of SIP might have feeds held as a result). Babies who had early feeding had less developmental delay at 20 months, (or, as the NICHD persists in calling it, ‘neurodevelopmental impairment': if I have to say it again, a low Bayley score is not an impairment!) and the association of early feeding with better Bayley scores, was seen whether or not the babies got prophylactic indomethacin.

The prophylactic indomethacin babies also did not have more NEC, and they had fewer PDA ligations. They also had much less frequent treatment with indomethacin or ibuprofen later in their hospital course, but the RR is reported as being over 1, and significant, which I don’t understand.

The early enteral feeds groups also had much quicker advancement to full feeds, and many fewer days of parenteral nutrition.

This confirms the RCT results, with a lot more babies but an observational study design, indomethacin doesn’t seem to increase SIP (despite our case-control findings) decreases PDA ligations, and adds very positive data about early feeds, at least starting feeds before 3 days of age. I think you should have a very good reason for not feeding a very preterm baby, such as shock requiring inotropes perhaps.

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Effects of (not very) NICE guidelines

Call me prescient, OK, you won’t, but I will. Two recent observational studies suggest that the recent NICE guidelines have had adverse effects on infants evaluated for potential early neonatal sepsis. ‘NICE’ of course is not an adjective for how good the guidelines are, but the acronym for the National Institute of Health and Care Excellence in the UK.

Any long time neonatalresearch watchers will remember vividly my perceptive analysis and critique of those guidelines. Which included the good (to stop antibiotics at 36 hours if no signs of sepsis) and the questionable; universal measurement of CRP at the start, with a repeat at 18 to 24 hours, and stopping the antibiotics if the trend is ‘reassuring’. My concern being that CRPs are relatively sensitive but with low specificity. Infants exposed to many different stressors, infectious and not, may have increased CRP. As early onset sepsis in term infants is relatively uncommon in most of the at-risk situations outlined, the proportion  of babies who have unnecessary prolongation of antibiotic therapy solely for a CRP which is not ‘reassuring’ might be substantial.

You have, of course, to balance that against the theoretical benefit of continuing antibiotics in an infant who is truly septic, in whom the antibiotics would have been stopped were it not for the non-reassuring CRP. A benefit which is likely to occur much less often.

Two recent studies have sought to quantify these impacts.

Mukherjee A, Davidson L, Anguvaa L, Duffy DA, Kennea N. NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014.

This is a before-after study which investigated the impacts on babies evaluated for possible sepsis.

I think this is from a single hospital in London (it is a short report so some details are missing, also weirdly there is not a single reference, not even to the NICE guidelines), and it appears that about 8-9% of babies had sepsis work-ups, with around 70 babies affected in each of the 2 month cohorts, before and after the NICE guidelines.

They looked at how many babies stayed in the hospital less than 72 hours, this decreased from 38.1% to 18.4%. More babies stayed over 5 days, from 20.9% up to 27.7%. They found that 58% of the repeat CRPs were used to change management, including leading to more LPs (14% up to 23%). In all of their babies there were no positive cultures.

We envisaged shorter hospital stays with new NICE standards, particularly, with the aim of 36 h blood culture reporting. However, repeat CRP led to further investigations, increased LPs and longer durations of treatment and stay. This, in turn, impacted on workload and cost, and influenced parental experience in the first few days of life

Naydeva-Grigorova T, Manzoor A, Ahmed M. Management of early-onset neonatal infections. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014.

This experience, published as a letter in Archives, recounts what happened with about 40 babies, before and after the guidelines. 1 of 40 before the guidelines had an LP, compared to 8 afterward. Entirely because the CRP was raised. Hospital stay increased after the guidelines, and duration of antibiotic use increased. None of the babies had positive cultures.

Our results indicate that babies in group B had prolonged hospital stay requiring longer duration of intravenous antibiotics without much clinical benefit.

I think there should be a rapid re-evaluation of these guidelines, which seem to be only having negative effects, at least from these 2 experiences. I think the reason that the NICE guidelines are not very nice is that the data being used to support the recommendation are based largely upon a single study from 1998, a good study from Bill Benitz in California, unfortunately (for the NICE guidelines) that study was not among asymptomatic babies, but only babies who had symptoms, the list of which includes shock, new apnea, lethargy, respiratory distress and so on, and also includes preterm infants down to 550 grams birth weight. It only included babies treated for sepsis in one of 3 NICUs. (See evidence table 10.3 in the guideline that you can find here). So it is of no relevance to the healthy full term baby with risk factors alone, in whom the false positives are clearly going to be much more frequent.

In the more recent study by Thierry Lacaze and colleagues, which only included asymptomatic infants being evaluated because of signs of sepsis, a single CRP at 18 hours of age had a PPV of 14% for proven or probable sepsis. I discussed the article when it first came out, and I think the suggestion of those authors, that a low CRP at 18 hours of age, using a method which gave a result immediately to the medical team, could lead to earlier stopping of antibiotics and earlier discharge is reasonable. The implication being that a non-reassuring CRP would then mean waiting until 36 hours and making a decision independent of the CRP.

For asymptomatic babies CRPs are too sensitive, being elevated for all sorts of reasons unrelated to sepsis requiring treatment.



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Responses to letters regarding our Journal of Pediatrics Probiotics article

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.


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.


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)


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

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

Stefan Johansson, who runs the NICU website/community 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

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

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 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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