Should we freeze maternal breast milk in the NICU? Pasteurize it?

Posted on 1 February 2017 by Keith Barrington

Maternal breast milk is what we should be giving to every preterm infant as much as possible. But we know that there are cases of transmission of cytomegalovirus (CMV) and reports of transmission of other pathogens to babies from breast milk. Transmission of CMV is probably very common, with some reports stating that as many as 37% of extremely low birth weight infants of seropositive mothers may acquire the virus from mothers milk.

I introduced universal freezing of breast milk (in 2001 I think) to our NICU when I was at the Royal Victoria Hospital following 2 serious cases of breast milk acquired CMV disease, we did that to try and reduce CMV transmission, but with the full knowledge that the evidence base was limited.

An overview of the literature I think shows that not much has changed since then. CMV acquisition by extremely preterm infants from maternal breast milk is common, most cases are asymptomatic, but there is an increase in BPD among babies who acquire CMV postnatally and there are occasional serious infections with hepatic dysfunction, persistent thrombocytopenia and pneumonitis. The most serious complications appear to be in the most immature infants, and in those who already have some liver or pulmonary injury. I reviewed some of the recent studies last year. Long term follow-up doesn’t show much neurodevelopmental impact, and also does not reveal an increase in deafness.

Freezing breast milk reduces CMV activity in breast milk, even 3 hours of freezing has an effect, but 72 is probably preferable, and, after freezing many samples will no longer contain viable, culturable CMV, and others have reduced activity.

However, there is no good prospective evidence that this reduces CMV acquisition, or prevents serious disease. It seems likely that if you reduce the viral load there will be fewer cases, and fewer cases of symptomatic disease, but that is not proven, and it may be that the overall reduction in viral viability is not enough to prevent transmission.

Also, a policy that all breast milk will be frozen prior to giving it to the babies will have an impact especially during the first few days of life, when a victorious mother arrives in the NICU with 3 mL of colostrum. If we then freeze and later re-thaw the precious liquid that will delay the infant receiving all the goodies, and it might also potentially harm transmission of infection protecting components even while reducing CMV load.

Our NICU at Sainte Justine until recently froze most breast milk brought to the NICU by parents, but did not routinely freeze during the first days when the volumes were low, so most babies received some non-frozen milk in any case. Later on, as stores increased, it was usual for the milk technicians to unfreeze a stored sample for the day’s feeds, newly arriving milk was frozen for later use.

Changes in our NICU milk kitchen have made us re-evaluate the practice.

Some recent articles about breast milk storage and handling have shown the following (many reviewed in  Peters MDJ, et al. Safe management of expressed breast milk: A systematic review. Women and Birth. 2016;29(6):473-81):

Lactoferrin concentrations are much higher  in human milk than in bovine milk (and almost absent in bovine milk based preparations), they are high in milk from preterm delivering mothers, and stay high for a couple of months.  (Turin CG, et al. Lactoferrin concentration in breast milk of mothers of low-birth-weight newborns. J Perinatol. 2017. Albenzio M, et al. Lactoferrin Levels in Human Milk after Preterm and Term Delivery. American journal of perinatology. 2016;33(11):1085-9.) Storage of EBM at usual freezer temperatures, -20 degrees, substantially lowers activity of lactoperoxidase, and immunoglobulin A, with a smaller impact on lactoferrin, and lysozyme. (Akinbi H, et al. Alterations in the host defense properties of human milk following prolonged storage or pasteurization. Journal of pediatric gastroenterology and nutrition. 2010;51(3):347-52.) But the impact on lactoferrin concentrations is still important (Raoof NA, et al. Comparison of lactoferrin activity in fresh and stored human milk. J Perinatol. 2015;36(3):207-9) prolonged storage leading to about a 50% drop in lactoferrin.

An observational study from Spain including 22 neonatal intensive care units suggested that freezing breast milk might be effective in reducing postnatally acquired CMV (Balcells C, et al. Vertically transmitted cytomegalovirus infection in newborn preterm infants. Journal of perinatal medicine. 2016. p. 485.)

We now know that breast milk contains probiotic organisms, as well as potential pathogens. In one study freezing at -20 for 2 weeks did not clearly affect bacterial CFUs, (Marin ML, et al. Cold Storage of Human Milk: Effect on Its Bacterial Composition. Journal of Pediatric Gastroenterology & Nutrition 2009;49.) and the probiotic organisms were still present after thawing, but the data I can find are limited, you can certainly imagine that the precise way the milk is frozen and thawed might have an impact on bacterial contamination. One study showed that freezing the thawing and rewarming breast milk led to lower bacterial counts, and the same group showed that bacterial colony counts continued to fall during 9 months of freezing.

One study showed that antioxidant activity of breast milk decreases during storage at -20, but not at -80, (Aksu T, et al. The effects of breast milk storage and freezing procedure on interleukine-10 levels and total antioxidant activity. The journal of maternal-fetal & neonatal medicine : 2015;28(15):1799-802) but another study contradicted that and found a reduction at -80 also.

Milk has bactericidal capacity, which decreases during storage and is better maintained after freezing than after refrigeration, especially after 48 hours.

What we need, of course is a randomized controlled trial, and lo and behold, there is one! Omarsdottir S, et al. Cytomegalovirus Infection and Neonatal Outcome in Extremely Preterm Infants After Freezing of Maternal Milk. Pediatric Infectious Disease Journal. 2015;34(5):482-9. In this study 140 babies less than 28 weeks gestation whose mothers were intending to breast feed were randomized to receive only frozen maternal milk, (at -20 for at least 72 hours) with pasteurized donor milk used during the first days until thawed breast milk was available. The control group received fresh breast milk as soon as possible, and did get some donor milk, they also received some frozen milk, as milk was kept refrigerated for a maximum of 72 hours, and then frozen for later use if necessary. There were 66 of the mothers who had detectable CMV in their breast milk. Of those there was a transmission rate of 8% (minor different between groups could have been due to chance, 9% frozen, 6% fresh). Of note, the intervention period lasted 6 weeks, and 2 of the CMV transmissions in the frozen breast milk group were detected after that period, when the babies had been receiving fresh milk, leaving only 1 (3%) who is known to have developed CMV during the frozen breast milk phase. None of the CMV cases appeared to be symptomatic. What this means, unfortunately is that the study is underpowered to detect a major potential impact on CMV transmission, but there was no evidence of protection found from freezing breast milk for the 1st 6 weeks of life on transmission of  CMV during the entire neonatal ICU stay. The study did find that the only cases of fungal sepsis were in the fresh breast milk group, from a secondary analysis of their data. Candida may be inactivated by freezing, according to the authors, but I can’t find the original data.

It may be that freezing to inactivate CMV is not as effective as previously thought, using very sensitive techniques one group found that samples were often still infective even after freezing. (Hamprecht K, et al. Cytomegalovirus (CMV) Inactivation in Breast Milk: Reassessment of Pasteurization and Freeze-Thawing. Pediatr Res. 2004;56(4):529-35.) Which may account for several case reports of babies who only ever received frozen-thawed milk, and still acquired CMV, apparently from the milk. To be certain what we should do we really need a much larger randomized trial, probably including only seropositive mothers.

At present I think that the evidence of protection from acquisition of symptomatic CMV infection by freezing and thawing of breast milk is lacking. There are potential adverse effects on immunologic components of breast milk, so we probably shouldn’t routinely freeze all maternal breast milk prior to giving it to extremely preterm infants.

Some countries recommend pasteurization of stored maternal breast milk (in France, for example). Holder pasteurization, heating the milk to 62.5 degrees for 30 minutes is the usual method (also used for milk banks in general). Holder pasteurization has major impacts on protein content of the milk severely degrading lactoferrin, lysozyme, immunoglobulins, reducing erythropoietin levels and cytokines, as well as epidermal growth factor and transforming growth factor. (for a complete review see ; Peila C, et al. The Effect of Holder Pasteurization on Nutrients and Biologically-Active Components in Donor Human Milk: A Review. Nutrients. 2016;8(8).)

Holder pasteurization does do what it is supposed to though, it does inactivate viruses, fungi, and bacteria. CMV is comprehensively inactivated by Holder pasteurization. Other pasteurization techniques (high temperature short duration) also inactivate the virus, and seem to have less impact on the immune characteristics of human milk, but aren’t widely used.

I have previously posted about the randomized controlled trial of pasteurization of mother’s breast milk, which actually showed a slight increase (potentially due to chance) in late onset sepsis compared to feeding fresh breast milk.

A new observational study from France, as part of Epipage2 (Dicky O, et al. Policy of feeding very preterm infants with their mother’s own fresh expressed milk was associated with a reduced risk of bronchopulmonary dysplasia. Acta Paediatrica. 2017.) showed that those NICUs that followed the national recommendation and pasteurized the milk of mothers of very preterm babies had more bronchopulmonary dysplasia. This was only shown on the adjusted analysis, whereas a possibly higher rate of NEC with raw milk from the univariate data disappeared on the adjusted analysis. They also did not show an effect on late onset sepsis.

With all of the major impact on human milk immune functions, I think that routinely pasteurizing maternal breast milk is not warranted, particularly in view of the lack of evidence of a benefit.

Final message, breast is best, and fresh is probably the best breast.

Posted in Neonatal Research | Tagged , , , , , | 5 Comments

Neonatal Updates

Posted on 30 January 2017 by Keith Barrington

McLanders ML, et al. The cognitive aids in medicine assessment tool (CMAT) applied to five neonatal resuscitation algorithms. J Perinatol. 2016.In many delivery rooms around the world, algorithms for neonatal resuscitation steps are posted on the walls. Do they help? Are they constructed to the best current standards? This paper reports an analysis of common algorithms, and the result is clear, there are serious limitations of all the available algorithms. Apart from a lack of clarity, and difficulty in using them during a real resuscitation, they are not even consistent with the standards on which they are supposedly based. Most end up on an infinite loop of administration of intravenous adrenaline, evaluation and re-administration of intravenous adrenaline. I hope the next step in the research of this group is to construct a better, clearer algorithm which does meet these standards. And then test whether it really helps resuscitation teams in the real world.

Logan JW, et al. Early postnatal illness severity scores predict neurodevelopmental impairments at 10 years of age in children born extremely preterm. J Perinatol. 2017. This study compares SNAP-II scores from babies in the ELGAN cohort and their neurodevelopmental outcomes at 10 years of age. Being very sick in your first 12 hours of life (SNAP-II more than 30, 23% of the subjects) increases the chances of lower scores on a range of neurocognitive tests. The differences are not enormous when expressed as the difference in the median z-scores (compared to population norms) but many are unlikely to be due to chance alone; many of the adjusted Odds Ratios show an increased Odds of the adverse outcome by a factor of around 1.6. There were also statistical associations with poorer social outcomes, and behavioural outcomes.

I don’t think that this necessarily means that the first 12 hours are critical for brain development, infants with higher early SNAP scores are more likely to have a range of other later complications also (such as necrotising enterocolitis), so the mechanisms behind this association are uncertain. Being very sick certainly is associated with an increased risk of a range of different outcomes, though.

Horne RS, et al. The Longitudinal Effects of Persistent Apnea on Cerebral Oxygenation in Infants Born Preterm. The Journal of pediatrics. 2017. This group from Monash University studied former preterm infants with polysomnography after they reached term. They included 24 babies between 27 and 36 weeks gestation at 2 to 3 weeks, 2 to 3 months and 5 to 6 months corrected age. They defined apneas as greater than 3 seconds (as long as not associated with periodic breathing). The studies lasted 2 to 3 hours on average, getting shorter as the kids got older, and therefore slept less. All of the babies had some apneas in all of the studies, about 250 total apneas on the 1st study falling to 150 on the 3rd. Average duration of the apneas was between 4 and 5 seconds, heart rates fell during the apneas by on average around 14 beats per minute, saturations fell by 2 to 4% and Brain oxygenation, measured by NIRS and expressed as the Tissue Oxygenation Index, fell by between 5 and 10% around the apneas, with the decrease being greatest at the oldest age.

I am not sure what this all means, the frequency of the apneas is actually quite similar to the frequency recorded in babies who had been full term, I don’t know if NIRS has been recorded in full term babies at these postnatal ages with apnea. It may be that the continuing pulmonary dysfunction in the ex-preterm baby makes them desaturate faster during an apnea, but I don’t know. Intermittent hypoxia  is associated with adverse outcomes in preterm infants, and this study shows it may persist for a long time. Is it associated with worse long-term outcomes? Is it affected by other treatments? Maybe we should be giving them caffeine until they stop having apneas at all, or until they go to school.

Thome UH, et al. Neurodevelopmental outcomes of extremely low birthweight infants randomised to different PCO2 targets: the PHELBI follow-up study. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2017. This is a neurological and developmental follow-up of 233 babies from the 311 survivors of the randomized trial of CO2 targeting from Germany. Bayley Scores of Infant Development were not different between groups, nor were neurological findings, nor anything else. Permissive hypercapnia seems safe from this analysis, even though the original publication of the trial did not show a clear advantage.

Posted in Neonatal Research | Leave a comment

Reducing antibiotic use in full term babies.

Posted on 27 January 2017 by Keith Barrington

Early onset neonatal sepsis currently has an incidence in North America among term infants of about 0.5 to 1 per thousand live births. But 15% of newborn infants have risk factors and they end up receiving antibiotics if current guidelines are followed. The group from Kaiser Permanente have developed an algorithm that could markedly reduce sepsis workups and antibiotic utilisation, they have tested this in their own population and showed that if their calculator was used many fewer babies required sepsis evaluations, and all babies who actually developed sepsis were evaluated and treated quickly.

The calculator they created is now available on-line.To use the calculator you need some data from the mothers course during labour and a physical examination  of the baby.

This new publication (Warren S, et al. Impact of neonatal early-onset sepsis calculator on antibiotic use within two tertiary healthcare centers. J Perinatol. 2016) is from an independent group who looked at all the babies who had a septic workup and antibiotic treatment in two hospitals, of the 205 babies most (92%) required evaluations and antibiotics following the CDC/AAP guidelines, but if the calculator had been used only 23% of them would have got antibiotics. They had no cases of actual culture-positive sepsis, seven patients were defined as having culture negative sepsis, and all were treated according to both CDC guidelines and the sepsis calculator. Although it seems a very reasonable approach, I think that fear of liability will prevent many people from using this calculator until the official guidelines change. They certainly need to change, when only 1 infant benefits from antibiotics for every 150 treated, the other 149 are only having adverse impacts of our current standards, including long-term effects on the intestinal microbiome. The consequences of missing a case, on the other hand, are important, and we need more data about the safety of using the calculator, preferably from a big enough sample to include some positive culture babies.

Posted in Neonatal Research | Tagged , | 2 Comments

How financial conflicts of interest affect medicine

Posted on 27 January 2017 by Keith Barrington

Ahn R, et al. Financial ties of principal investigators and randomized controlled trial outcomes: cross sectional study. BMJ. 2017;356.

Not neonatology but a study of how principal investigators’ financial ties to the pharmaceutical industry are associated with outcomes of controlled trials of drug efficacy funded by either industry drug wholesalers or non-industry sources. The authors searched Google with the name of the PI and the drug company producing the medication being tested in a randomized controlled trial, they also used a couple of databases to identify the financial links between investigators and drug companies. Two thirds of the PIs had some financial ties with the companies producing the drugs that they were testing.

Of all principal investigators, 156 (39%) reported advisor/consultancy payments, 81 (20%) reported speakers’ fees, 81 (20%) reported unspecified financial ties, 52 (13%) reported honorariums, 52 (13%) reported employee relationships, 52 (13%) reported travel fees, 41 (10%) reported stock ownership, and 20 (5%) reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% (103/136) among positive studies and 49% (29/59) among negative studies. In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome (odds ratio 3.23, 95% confidence interval 1.7 to 6.1). In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for the study funding source (odds ratio 3.57 (1.7 to 7.7).

Most of the financial ties were not clearly reported on the primary publication. Even for publicly funded trials financial links with industry are associated with a much higher chance that you will show that the drug that you have a vested financial interest in is effective. I don’t know what we can do about such things, realistically. I have received travel expenses (usually indirectly through the organizing committee of a conference) from industry (specifically from Mallickrodt and from Chiesi) . I think we should make more effort to be transparent about all of these links, and more effort to reduce them and make them more arms length also.

Two other articles address related issues this week, the first (Lin DH, et al. Financial conflicts of interest and the centers for disease control and prevention’s 2016 guideline for prescribing opioids for chronic pain. JAMA internal medicine. 2017) examined comments sent to the CDC following release of a new guideline which aimed to restrict opioid prescribing in the hope of having an impact on the current epidemic of opioid related deaths in the USA (which is spreading across Canada also, from Vancouver in our direction). There were 158 organisations who submitted comments about the draft guidelines, one third of them received financial support from opioid manufacturers, those organisations were much more likely to be negative about the guideline, (although many were positive and some submitted suggestions to improve). Organisations were not required to state any potential conflicts when submitting comments so these authors also had to do a bit of detective work to find these links.

The CDC should require commenters to reveal their potential conflicts of interest.

Another article examined financial conflicts of interest among Hematologist-Oncologists who use Twitter, although we don’t know what they were tweeting about in this study, other research has shown that physicians using twitter tweet about medical subjects more than 60% of the time and often mention drugs or medical products. They found that 80% of the Twitter active Hematologists had a financial conflict of interest. I don’t think that there are many who report, or have a link to a report of, their potential conflicts of interest.

Twitterers beware!

 

Posted in Not neonatology | Leave a comment

Happy New Review no. 2; Inhaled NO in the full term infant

Posted on 17 January 2017 by Keith Barrington

We have also updated the Cochrane review of inhaled NO in the term infant. (Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane database of systematic reviews (Online). 2017;1:CD000399). This was also a major update, with the addition of 3 trials, but also a restructuring of the review. On adding the trial from Gonzalez, which was a trial of early compared to late NO in 2 hospitals in Chile without access to ECMO, we re-thought several of the other trials that we had previously analyzed as being trials of NO which allowed backup treatment of the controls with NO. In fact there were 6 trials in total which had criteria for enrolment, and randomized babies to immediate inhaled NO, or to a control group who would receive inhaled NO if their oxygenation worsened to more severe criteria.

We have now analyzed those 6 trials (Barefield 1996; Day 1996; Sadiq 1998; Cornfield 1999; Konduri 2004; Gonzalez 2010) as comparisons of early compared to late intervention with NO.

The risk of bias figure, including all the trials, is below:

risk-of-bias-summary

For several of the trials the funding source was not clear, hence the  question mark, but for several which are marked by the question mark in yellow, including for example Konduri 2004, funding was primarily from a government granting agency, but there was also partial support from industry, with the manufacturer of inhaled NO providing the gas (and placebo) free of charge for the trial.

For the first comparison, inhaled NO versus control, studies which did not allow back-up treatment with NO in controls, the results of the analyses are unchanged. Inhaled NO is clearly beneficial in terms of reducing the need for ECMO, with an NNT of about 5.

We now present in the review a second comparison, inhaled NO at moderate compared to severe criteria for illness severity. The Summary of Findings table looks like this:

no-in-the-term

The actual criteria for illness severity were not consistent between trials, moderate severity was either based on Oxygenation Index (between 15 and 25, or 25 to 35 or 10 to 30) or on AaDO2 of 500 to 599. Whereas severe criteria were if they passed the upper limit of those ranges; so greater than 25 or 35 or 30 or an AaDO2 of 600 or more. I think there is enough overlap in the qualifying criteria that the studies satisfy Barrington’s rule, and that it is reasonable to meta-analyze them. But I realize that others may have a different response to that.

The overall message is that there is no proven advantage in clinical outcomes (death or needing ECMO) of starting NO earlier, compared to waiting for more severe criteria of illness severity. Fewer infants will progress to severe criteria if you start NO early, but if you wait until they become more hypoxic they will still respond.

There are, as always, some limitations to that statement, the confidence intervals are very wide, and include a possibility of a substantial relative reduction in mortality, (or a large increase). The absolute numbers dying, for example are 10% in the group who were treated at severe illness criteria, this might change to between 3.8% and 12.6% if the babies are treated earlier.

I don’t think based on these numbers that any promotion of the earlier use of inhaled NO can be justified. You will treat 100% of babies at moderate illness criteria, compared to treating about 60% of them if you wait for more severe criteria, which will have an impact on resource utilisation, but no evident impact on clinically important outcomes.

Posted in Neonatal Research | Tagged , , | Leave a comment

Happy New Year! And Happy Reading; an update of the Cochrane review: nitric oxide in the preterm

Posted on 13 January 2017 by Keith Barrington

A major revision of the Cochrane review of inhaled nitric oxide gas in the preterm infant is now available. (Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane database of systematic reviews (Online). 2017;1:CD000509). It includes 2 new publications, a small RCT from China, and the large multicenter RCT in preterm babies still requiring respiratory support at 5 to 14 days: the NEWNO trial (listed in the review as Yoder 2013). This was an unusual situation for me as the NEWNO trial has still not been published; we waited a while to finalize the review as we thought that it would be better that NEWNO was in print before including it in the meta-analysis. Eventually, because we had access to much of the summary data, we decided, with the delays in publication of the primary data for the entire study, that we should proceed. It is possible of course that we may need to make some minor adjustments to the review once the peer-reviewed publication appears, but it is unlikely, I think, that there will be any major changes to make. The main conclusions are very likely to stand.

One of the great things about Cochrane reviews is that they are (supposed to be) kept up to date. With frequent new literature searches and inclusion of new trials as they appear. Which means that authoring a review is a serious commitment. Also this time for the new reviews there are a number of innovations in the Cochrane Collaboration standards since the last time I updated the review. As well as the graphics to show the risk of bias evaluations, each new review (or updated review) will have a Summary of Findings Table, using Grade standards (and the Grade groups on-line software).

In case you haven’t seen them before here is one of the risk of bias figures: it should be clear that this is really what is meant, not that there has been bias, but that a lack of allocation concealment (for example) increases the risk of bias. For this review, many of the trials were funded by industry (previously not a common occurrence in neonatology) so we decided to add the column entitled ‘Funding Source’. There are abundant data to show that industry funding skews the medical literature, I therefore think we should have such a column for all Cochrane reviews, but we must be clear that although this increases the risk of bias, it doesn’t necessarily mean that those trials marked in red were actually biased. By most standards, in fact, the industry-funded trials in this review appear to have been free of the problems with many such trials, like inappropriate composite short-term outcomes, controls groups almost designed to have poorer outcomes, selective publication and selective reporting of outcomes.

cochrane-premie-no

The Summary of Findings tables are newer, and follow GRADE standards for determining how much confidence we have in the findings. This is the SoF table for the new version of this review.

no-preterm-sof-table

As you can see, the summary is that there is no evidence of benefit from the use of inhaled NO for any of these indications in the preterm. The situation where the potential benefit is closest to being statistically significant is the use of inhaled NO for infants older than 3 days who are determined to be at elevated risk of BPD. One of those studies was somewhat different to the other 2 in that category, the study by Subhedar, but that trial only contributed about 40 of the over 1000 subjects, so we did a sensitivity analysis, eliminating that study, which still shows an effect consistent with chance.

no-preterm-forest-plot

I also applied the Barrington rule, which is that if it was not possible to be eligible for 2 studies, they shouldn’t be meta-analyzed, Subhedar’s study included babies at 96 hours, the other two studies were minimum 5 days of age, and those two had considerable overlap in eligibility. So the 2 larger studies satisfy the Barrington rule, but not the smaller one.

So is this the final word? Does this mean that it is never justified to give inhaled NO to a preterm infant? My response to my own question is that I think that the evidence is consistent with a statement such as “the data currently show that the administration of inhaled NO to critically ill preterm infants in the first few days of life, with hypoxic respiratory failure, does not lead to an overall increase in survival”. That is not the same as saying that there are never any indications for a trial of inhaled NO, especially when there are clear indications of pulmonary hypertension.

Some groups of preterm babies have not been adequately studied, for example, preterm infants with clear evidence of pulmonary hypertension. Such infants may have a poor response to surfactant, and have a severe pre- to post- ductal oxygenation gradient, they often have a dramatic immediate response to inhaled NO, just like babies at term. It seems unreasonable to withhold NO from such a baby at 33 weeks gestation, when an otherwise identical baby at 35 weeks gestation would receive the treatment. Our individual patient data meta-analysis suggested that there may possibly be a benefit to using inhaled NO in preterm babies with pulmonary hypertension, but the interaction term was not statistically significant, and there were very few babies for whom pulmonary hypertension had been recorded in their original data files, and there was not a clear, consistent definition of pulmonary hypertension either.

I do think there is room for more trials in the preterm. An ethically justifiable trial would include preterm babies with good evidence of pulmonary hypertension, and would allow rescue treatment in the controls if they continued to be hypoxic after an interval, such as 60 minutes. Current data show a high frequency of intracranial hemorrhage in preterm babies with apparent pulmonary hypertension who receive NO; and I think it is possible that the sudden improvement in pulmonary vascular resistance, and sudden increase in cerebral perfusion that accompanies this change, could cause an increase in IVH. It might be that just being more patient, and awaiting a more gradual diminution in pulmonary artery pressures may lead to better outcomes. Hence a trial would be appropriate, and I think needs to be done. My opinion is not the same as the group that published some recommendations in March last year (Kinsella JP, et al. Recommendations for the Use of Inhaled Nitric Oxide Therapy in Premature Newborns with Severe Pulmonary Hypertension. The Journal of pediatrics. 2016;170:312-4) they stated that performing an RCT in such babies was not feasible, but I don’t understand why not. We have done studies in near-term babies who were near-death, and proved the value of inhaled NO. All we currently know in the preterm baby with PPHN and inhaled NO is that many of them have acute short-term responses, we have no evidence of improvement in survival or serious long-term consequences.

The other group of preterm babies for whom inhaled NO is currently frequently used are those babies who are developing severe chronic lung disease and go through periods of very poor oxygenation. Those babies also frequently have at least a partial response to inhaled NO, and I think a trial in such babies to determine if NO is actually beneficial for clinically important outcomes would also be justified.

Posted in Neonatal Research | Tagged , , | Leave a comment

You can’t diagnose reflux with a laryngoscope!

Posted on 23 December 2016 by Keith Barrington

I have seen in several places, and heard other neonatologists from elsewhere make comments about, a very high frequency of the diagnosis of serious reflux by ENT surgeons. Almost every time a consultation is requested, for almost any indication, the ENT team will make a diagnosis of reflux and recommend therapy. We often joke that an ENT consultation that does not mention reflux would be worth publishing as a case report!

This study is in children who were outpatients at Boston Children’s Hospital being evaluated for chronic cough with laryngoscopy, esophagoscopy/gastroscopy and esophageal impedance. (Rosen R, et al. The Edematous and Erythematous Airway Does Not Denote Pathologic Gastroesophageal Reflux. The Journal of pediatrics. 2016).
77 consecutive patients were enrolled, and 3 pediatric ENT surgeons of varying years of experience reviewed the videos of the laryngoscopy. They used a “reflux findings score” which is repeatedly referred to in the article as being “validated” but I don’t have any idea what they mean by this, as they note that there is a great deal of inter-rater variability in the score when used in adults, and that it doesn’t relate to objective measures of reflux in adults either. So validated I guess just means that it is a score, “this score which I have created, which is mine— is mine”.

The ENT surgeons in the study gave scores for each of the characteristics of redness oedema, presence of thick mucus and 5 other features. The children (average age about 6 years) then had combined pH with Multiple Intraluminal Impedance monitoring, the gold standard for detecting reflux, and for how high the reflux travels, if it gets anywhere near the larynx.

You can probably guess the results, but one image speaks a thousand words (which won’t stop me typing the words as well).

Print

Absolutely no correlation between the scores, the RFS, and any measure of reflux that they examined. Also there was almost no agreement between ENT surgeons. They tried really hard, by creating new pediatric subscores of the RFS, and still couldn’t find anything. No correlation between the entire score or any subset of the score and number of reflux events, percentage of time with reflux, acid reflux alone or anything. In fact, with all the correlations that they looked at they risked finding something by chance alone, but they didn’t.

They also looked at the correlation between oesophageal inflammation on biopsy and the RFS and again found nothing.

There are 2 previous studies which have basically said the same thing, but this one had the best methodology.

Next time you ENT surgeon tells you a baby has reflux, just gently and politely tell them that you can’t diagnose reflux with a laryngoscope, either in children or in adults.

This article does have some other information that was new to me. ENT surgeons in the USA are among the biggest prescribers of Proton Pump Inhibitors in children, and the total cost of diagnosing and treating reflux in adults alone in the USA is 50 billion dollars a year. Equivalent to the costs of cancer.

The children in this study did have a reasonable indication for the investigations, but the only way to tell if a child, or a baby, has more than average reflux is with prolonged ph-MII recording. But of course, even that doesn’t tell you if the reflux is pathological, just how much of it there is.

Posted in Neonatal Research | Tagged | 1 Comment

Venous catheters and thrombosis, risk factors, consequences and treatment.

Posted on 23 December 2016 by Keith Barrington

We had a journal club for the fellows lately, everyone had to find an article about venous thrombosis and association with central catheters. We chose the topic because seem to have many more thromboses than in the past, whether that is due to an increasing sensitivity of routine ultrasound, or if the incidence is truly increasing. I don’t know if there has been some change in practice or in catheter materials or in the relative size of the catheters now that we use mostly multi-lumen catheters, but we certainly have a lot more babies for whom we consider anticoagulation, and sometimes do it.  This certainly was not a systematic review, but an attempt to get an overview of incidence and risk factors, of what are the consequences at short and long-term, and whether anyone knows what are the indications for treatment and whether treatment should be anticoagulation (and if so with what) or thrombolysis, and whether treatment makes a difference in the long term.

Kim JH, et al. Does umbilical vein catheterization lead to portal venous thrombosis? Prospective US evaluation in 100 neonates. Radiology. 2001;219(3):645-50.

This is chronologically the first of the studies, the authors prospectively enrolled 100 babies with umbilical catheters, and then repeatedly ultrasounded them during and after catheter removal, specifically being interested in Portal Venous thrombosis, and then repeatedly until the clots resolved or the baby was discharged. They found 43% of them had thromboses, which were more likely if the catheter was in place for more than 6 days, and if it had been used for a transfusion. It looks like the presence of the catheter in the portal vein increases the risk (up to 62%). They divided the clots into occlusive and non-occlusive; the occlusive ones were less likely to resolve, 69% of them were still present at discharge. They didn’t treat with anticoagulants, and 70% of the non-occlusive clots resolved. Position of the catheter tip was not statistically significantly associated with thrombosis, but 63% of catheters which had been in the portal vein developed thrombosis, the lack of significance may just be an issue of power. Catheter duration over 6 days was also a risk factor.

Narang S, et al. Risk factors for umbilical venous catheter-associated thrombosis in very low birth weight infants. Pediatr Blood Cancer. 2009;52(1):75-9.

This study was a secondary publication from an RCT of umbilical catheter duration, infants were prospectively evaluated with ultrasound for central catheter related thromboses. 11% of the approximately 200 infants developed a UVC-related thrombosis, a high hematocrit (over 55%) was the only factor, on adjusted multivariate analysis, associated with increased risk. In the original trial (comparing use of UVCs for 7 to 10 days followed by a picc, to use of UVCs for up to 28 days) there were 13% with thrombi in the long-term group, and 9% in the short-term, none were occlusive.

Morag I, et al. Portal vein thrombosis in the neonate: risk factors, course, and outcome. The Journal of pediatrics. 2006;148(6):735-9.

This is a retrospective cohort study of children admitted to the Toronto sick kids’ hospital NICU who had a diagnosis of portal vein thrombosis. They had 133 infants over 4 years, 73% of their infants had a UVC, and the majority of those who developed a thrombosis had a low or intrahepatic catheter position. Many of their patients progressed to lobar hepatic atrophy or portal hypertension (26% and 3% respectively). They also present a grading system, infants with more severe grades were more likely to develop those complications, and infants with mal-positioned UVCs were also more likely to develop complications. Many of their diagnosis were made when an abdominal ultrasound was performed for non-specific indications (babies with malformations or evaluation of hypertension) thrombocytopenia was relatively common at the time of the diagnosis. The authors could not find any indication that anticoagulation, which was given to about half of the babies, changed the outcome. They anticoagulated babies with a second thrombus, who had cardiac surgery, or who had a grade 3 thrombus.

This is their image showing the grading system.

portal-vein-thrombosis-grade

Shah PS, et al. A randomized, controlled trial of heparin versus placebo infusion to prolong the usability of peripherally placed percutaneous central venous catheters (PCVCs) in neonates: the HIP (Heparin Infusion for PCVC) study. Pediatrics. 2007;119(1):e284-91. This one is a little different, an RCT of heparin in picc lines, which showed that heparin prevents thrombosis of the catheter itself, but there is no evidence that it changes the rate of catheter associated central vein thrombosis (which occurred in 18% in each group, and were all non-occlusive). Which is very similar to the data from umbilical arterial catheters Barrington KJ. Umbilical artery catheters in the newborn: effects of heparin. Cochrane database of systematic reviews (Online). 2000(2):CD000507 heparin in UACs prolonged catheter patency, but did not affect arterial thrombosis rates. I also found one small trial of heparin for umbilical venous catheters (Unal S, et al. Heparin Infusion to Prevent Umbilical Venous Catheter Related Thrombosis in Neonates. Thrombosis Research. 2012;130(5):725-8.) there were only 19 babies in the heparin group (and 27 controls) with one control baby developing a thrombosis. Clearly not significant statistically, but woefully underpowered.

Park CK, et al. Neonatal central venous catheter thrombosis: diagnosis, management and outcome. Blood Coagul Fibrinolysis. 2014;25(2):97-106. This is a literature review, giving an overview of the topic and trying to synthesize the information from the mostly observational studies, many of which report different outcomes, and had different methodologies for detecting thrombi. They couldn’t find any reliable evidence that anticoagulation improves outcomes after a catheter associated thrombosis, they describe one study which reported the use of urokinase for catheter associated central venous thrombosis, about half of the clots resolved with this intervention but there were no controls.

Bohnhoff JC, et al. Treatment and follow-up of venous thrombosis in the neonatal intensive care unit: a retrospective study. J Perinatol. 2016. In this retrospective study the authors treated about 2/3 of the 26 central venous thromboses with low molecular weight heparin, the others had contra-indications to therapy. Doses needed were higher than the current recommendations especially for the preterm babies, some of the thromboses resolved, some of the babies were still treated after discharge. There were no hemorrhagic complications. There really isn’t any evidence from this study that the enoxaparin made a difference.

Saracco P, et al. Clinical Data of Neonatal Systemic Thrombosis. The Journal of pediatrics. 2016;171:60-6 e1. This is a report from an Italian registry, and includes 75 babies with systemic thrombosis, including arterial, venous and intracardiac thromboses. It really wasn’t very helpful for answering any of our clinical questions.

Finally, this article wasn’t discussed in our journal club, but it reports long-term outcomes from the sick kids cohort of portal vein thromboses (PVT). Morag I, et al. Childhood outcomes of neonates diagnosed with portal vein thrombosis. Journal of Paediatrics and Child Health. 2011;47(6):356-60. They found outcome data for 70 babies, and the duration of follow up was 2 to 8 years (LLA is hepatic left lobe atrophy). They conclude

…28% still had asymptomatic LLA in childhood, 7% had slowly progressive splenomegaly and 3% required shunting because of progression of portal hypertension. Ultrasonographic follow up was the most sensitive method in detecting progression associated with neonatal PVT. Until more data are available, periodic long-term ultrasonographic follow up should be considered for neonates diagnosed with PVT.

So what does this all mean? It is clear that central venous catheters can lead to central vein thrombosis, the major risk factors appear to be malposition of an umbilical venous catheter in the portal vein branch, and probably polycythaemia. Some children develop long-term complications of a thrombosis, with as many as 2 to 3% perhaps having portal hypertension, if the progressive splenomegaly is a sign of incipient portal hypertension then the incidence may be much higher. The anatomy of the region is complicated, and in fact looking for an image on google, representations of the anatomy are often wrong. This is a diagrammatic representation which I found here.

umbilical-vein-anatomy

Malpositioned umbilical venous catheters therefore often pass into the left branch of the portal vein, which may then become thrombosed decreasing perfusion of the left lobe of the liver. I am not sure why low catheters should have a higher risk of thrombosis than catheters in the ductus venosus or IVC, but that does seem to be the case in some studies, but not consistently. One idea for that association is that low catheters are often low because they won’t advance properly, and may have entered the portal vein during attempted insertion leading to endothelial damage and initiating thrombosis. It would be interesting to see if catheters intentionally inserted low (such as for resuscitation) also have an increased risk of thrombosis. Umbilical catheters left in place for more than 6 days also are more frequently associated with thrombosis, that agrees with the data from the RCT of UVC duration that I cited, where thrombosis recognition was after 5 days.

It isn’t clear to me that anticoagulation makes any difference, and I think that non-occlusive thrombi can probably be watched without therapy.In fact there is no good evidence that either heparin or LMWH improve outcomes for any site of thrombosis in the newborn as a very recent Cochrane review makes clear.

Occlusive and especially grade 3 thrombi have a higher risk of long-term adverse effects, but whether heparin, low molecular weight heparin (LMWH), or thrombolysis make any difference is not clear; LMWH can usually be given relatively safely, requires less monitoring as dose requirements are more predictable, and can be given intermittently. Thrombolysis always makes me anxious, I think it should be reserved for the most problematic thrombi, such as intracardiac cases.

So here are a few propositions, some are obvious some are speculative:

  1. Umbilical venous catheters should not be left in the portal vein.
  2. Umbilical venous catheters which are malpositioned (including low catheters) should be removed as soon as practicable
  3. Malpositioned UVCs should be followed by ultrasound evaluation of the portal venous system after removal
  4. Correctly positioned UVCs should be removed after about a week
  5. I question if all UVCs should be followed with ultrasound after removal or not, I think more prospective observational data are required. Perhaps well positioned catheters in non-polycythemic babies that are removed before 7 days might not need an ultrasound.
  6. Non-occlusive thrombi can be observed without anticoagulation
  7. Occlusive thrombi of grade 2 can probably be observed without therapy, but an RCT of LMWH would be very useful.
  8. Occlusive thrombi of grade 3, an RCT comparing no therapy, LMWH and thrombolysis (with rTPA) is needed, with long-term follow-up.
  9. Thrombi which are potentially dangerous in the short term (such as intracardiac) should be treated with rTPA
  10. For peripherally inserted central catheters no routine ultrasound is required (although frequent small thrombi are found, large clinically important thrombi  are rare)

I just searched clinicaltrials.gov and there doesn’t seem to be any relevant controlled trials of heparin or LMWH in the newborn. Off-label use of the LMWHs is quite frequent, so an RCT or 2 would be feasible within a research network.

Posted in Neonatal Research | Tagged , | 2 Comments

Inhaled steroids for BPD?

Posted on 12 December 2016 by Keith Barrington

In a recent post I promoted a new Barrington rule for meta-analysis (it probably already existed somewhere but I am claiming priority anyway, it’s a “post-truth” kind of thing). The rule was that in a systematic review you shouldn’t pool data from 2 (or more) studies if it was impossible to be eligible for all the studies, in other words, if there is no overlap in the eligibility criteria. For example in the systematic review of inhaled NO in the preterm, there were studies of early rescue use for critically ill babies, and studies of much later use in relatively stable babies. Combining all those studies makes little sense as it doesn’t answer any clinically useful question. If you want to know about the proven effects of early use of inhaled NO for a 12 hour old baby who is needing 100% oxygen, then adding into the analysis studies of babies who were studied because they were on CPAP at 2 weeks of age is really unhelpful, and will only muddy the waters.

Which is why I really don’t understand the rationale for mixing together several of the studies in this new meta-analysis and systematic review

Shinwell ES, et al. Inhaled Corticosteroids for Bronchopulmonary Dysplasia: A Meta-analysis. Pediatrics. 2016.

The authors have included trials that studied :

(1) preterm infants of gestational age 22 0/7 to 36 6/7 weeks considered to be at risk for BPD, including both ventilated and nonventilated infants and (2) an RCT comparing any Inhaled Corticosteroid versus control (placebo or no treatment) at any dose and any duration of treatment and administered either by a metered-dose inhaler or by nebulization.

 

Which means they included studies with very early enrollment studying prophylaxis, other studies enrolling at 2 weeks of age of babies still intubated and with early BPD changes, and even one study that enrolled babies at 14 weeks of age who had already failed extubation and were needing more than 40% oxygen. I can’t imagine a clinical situation in which it would be useful to know the effects of inhaled steroids from all of those studies pooled data.

Most of the 16 included studies were tiny, with only 2 enrolling more than 100 babies, and most being around 30. Meta-analyzing multiple small studies risks inflating effect sizes. That isn’t the SR authors fault, but it is a problem with many neonatal systematic reviews.

The major primary outcome of the meta-analysis of Death or BPD at 36 weeks GA was based on 6 studies which are mostly somewhat similar to each other, and enrolled babies in the first 3 days of age (either on day one or on day 3) except for the study by Cole, which entered babies between 3 and 14 days of age. Bassler’s trial was a trial of prophylaxis in any baby needing assisted ventilation, whereas the others mostly needed some severity of illness criterion.

f1-large4

As I posted at the time that Bassler’s study was published that outcome is quite problematic, lung injury is a continuum, and forcing it into a dichotomous outcome for simplicity of reporting or analysis is rather unhelpful. Oxygen stopped at 35 weeks and 5 days, = no BPD, oxygen stopped 2 days later = BPD, even though the baby out of oxygen just before 36 weeks may have more signs of tachypnoea, retractions etc. Our recent publication (Janvier A, et al. Measuring and communicating meaningful outcomes in neonatology: A family perspective. Semin Perinatol. 2016) discusses this in some detail, and noted:

Many pulmonary outcomes having a negative impact on neonates and their families, such as rehospitalisation, needing oxygen therapy at home, and visits to the emergency department, are not systematically reported. A description of the impacts of the lung injury beyond a dichotomous BPD outcome would be much more useful, both to parents and to the health care professionals who care for them.

Although it is possible that very early inhaled steroids really do reduce oxygen requirements at 36 weeks, I am not sure this systematic review meta-analysis helps us know.

If you have a very preterm baby who is on respiratory support on the first day of life, and you want to know whether you should give inhaled steroids to reduce lung injury then the results of the studies in that Forest plot above from Yong, Fok and Bassler are relevant. In contrast, if the baby is not extubated by day 3 then the other studies are relevant, (Cole, Jangaard, and Merx). And even with all the data from both groups of studies that have non-overlapping eligibility criteria, the 95% confidence intervals are very close to 1.0.

So this isn’t really conclusive data, even about that outcome, death or BPD (of note there is no hint of an effect on death, the part of that outcome which is affected is the need for oxygen at 36 weeks), and as I said, I really don’t think it’s that important an outcome, unless, in this group, the diagnosis of BPD reflects worse pulmonary disease-related quality of life. What is now called moderate or worse BPD (i.e. oxygen for at least 28 days and still needing oxygen at 6 weeks) is associated with slightly worse long-term pulmonary function during the first year than mild BPD or no BPD, the differences are, however, not enormous. But just because a particular intervention decreases O2 requirements at 36 weeks doesn’t necessarily mean that those other clinically important outcomes (hospital re-admission, chronic pulmonary medication use etc) will be affected also. What I mean is, that steroids may reduce inflammation and have multiple effects on the lung, some of which might be negative, but unless they improve long-term lung function the baby hasn’t necessarily benefited.

I hope this Systematic review doesn’t lead to widespread use of a therapy for which the data are currently very limited, the excellent NEUROSIS trial will hopefully provide data about longer term pulmonary outcomes of their babies, to know if there is a benefit that will have an impact on the babies’ lives, and their families.

 

Posted in Neonatal Research | Tagged , , | Leave a comment

Toxicity of reflux medications in infancy

Posted on 2 December 2016 by Keith Barrington

Before I leave the topic for at least a few days, I thought I would discuss data about the toxicity of reflux medications in older children. Most of my ‘toxic placebo’ comments have been about studies in preterm infants, and one of the major secondary effects of anti-acid medications in preterm infants is an increase in necrotizing enterocolitis and in systemic sepsis, neither of which are likely to be very common in older children. But there is in fact, also good evidence that anti-acid medications increase infections, at least respiratory infections, in older children.

Orenstein SR, et al. Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial Assessing the Efficacy and Safety of Proton Pump Inhibitor Lansoprazole in Infants with Symptoms of Gastroesophageal Reflux Disease. The Journal of pediatrics. 2009;154(4):514-20.e4.  160 infants less than a year of age were randomized to lansoprazole or placebo if they had “symptoms of GERD”. There was no improvement in symptoms or any of the primary or secondary outcomes. There was however, an increase in serious adverse effects from 2% to 12%, the most common of which were lower respiratory infections.

Writing Committee for the American Lung Association Asthma Clinical Research Centers. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA. 2012;307(4):373-81. This multicenter trial was performed because of a widespread belief that acid reflux was responsible for triggering episodes of asthma, and anti-acid medications were frequently prescribed. Over 300 children were randomized (aged 6 to 17), and the proton pump inhibitor did absolutely nothing good. There was no improvement in any symptom, or any primary or secondary outcome. In contrast the children on the active drug had more respiratory infections (number needed to harm = 7) had more sore throats and had more than twice as many episodes of bronchitis (NNH=14).

The data from these 2 RCTs confirm  a prospective non-randomized study in 100 infants started on anti-acid drugs by pediatric gastroenterologists, both ranitidine and omeprazole were studied. There were significant increases in both gastroenteritis (from 20% to 47%) and pneumonia during the 4 months of treatment compared to the period before, and compared to the (non-randomized) controls. An observational study in adults also showed an increased risk of community acquired pneumonia.

So acid suppression doesn’t work for symptoms attributed to GERD  in older infants either, and the medications increase risks of infectious disease in infants, children and adults.

Metoclopramide has a poor safety profile with dystonic reactions, oculogyric crisis, irritability, drowsiness, emesis and apnoea occuring in 9 to 15% of patients, it also has not been shown to improve reflux, and indeed in a neonatal mammalian model, didn’t even have prokinetic effects.

Domperidone worsens GE reflux in newborns and has no beneficial effect in older children, it may prolong the QT interval; it is not thought to cross the blood brain barrier in older children, but the relatively ‘leaky’ BBB in babies might be another matter entirely.

So the data about efficacy and safety are very similar in older infants as in preterm babies: no good evidence of any benefit of any of the medications, and reliable evidence of harm.

They are still toxic placebos after hospital discharge.

 

 

Posted in Neonatal Research | Tagged , | 2 Comments