Breast = best: past your eyes?

The title is from one of those bad punny jokes that you never forget, about taking a bath in milk (pasteurized? No just up to my chin. Boom, boom). For the readers of this blog who are not native English speakers, just ignore this first paragraph and go on to the next.

This is I think a unique study, (Cossey V, Vanhole C, Eerdekens A, Rayyan M, Fieuws S, Schuermans A: Pasteurization of Mother’s Own Milk for Preterm Infants Does Not Reduce the Incidence of Late-Onset Sepsis. Neonatology 2012, 103(3):170-176the authors from Leuven in Belgium randomized 303 babies (<32 weeks or <1500 g) who were getting maternal breast milk to either get it raw or to have it pasteurized first. This is something which has often been discussed, does pasteurizing milk reduce its anti-infective properties? We have often asked the question because donor milk from milk banks is pasteurized, and we wonder if it will still have the benefits that human milk has before you pasteurize it. We know that pasteurized milk still reduces NEC, as the studies by Alan Lucas from many years ago used pasteurized donor milk in some babies, and they still had the benefits. The data about breast milk and hospital acquired infections aren’t as strong, much less good data in the literature, and the Cochrane review comparing breast milk to formula only includes data from one study, which showed no effect. But we think that human milk feeding probably also reduces some late-onset infections in the preterm baby in an NICU.

We also know that breast milk is not sterile, it is often contaminated with staphylococci, and other organisms which have on occasion been implicated as causing invasive infections. So the authors compared systemic infections between babies that got the pasteurized or raw milk.  The way the title is written is a bit strange, as in the introduction the authors state that they hypothesized that pasteurizing breast milk reduced its benefits as an anti-infective agent, but the title refers to the opposite effect. And, if their hypothesis really was that pasteurization was bad, then there is an ethical issue: why would you test something that is difficult to organize and study, and is not standard practice, if your hypothesis is that it is bad? I think more realistically, that there was real equipoise (which hasn’t been expressed properly), that pasteurizing breast milk may have good effects (reducing the risk of bacterial colonization) and/or bad effects (inactivating immunoglobulins and adversely affecting other important proteins).

The findings of the study were generally negative, that is there was no big difference in any outcome between the groups. What they did show was the there were more infections in the group that received pasteurized milk. A modestly sized increase, compatible with a chance effect, 15% of the babies who received raw milk had at least one infection, compared to 20% of the group who got the ‘past-your-eyes’ stuff. The p value was 0.23. Which is not significant by conventional thresholds, but here again we must question these conventions. Wouldn’t it be more informative for everyone reading this article to state, rather than ‘not significant’ something like the following: ‘there is a 2 in 9 probability that the increase in infections in the pasteurized milk group could have arisen by chance’. Which means in fact, that this ‘non-significant’ result is more likely to be real than not, there is a 7 in 9 chance that the increase in infections is a real difference between the groups.

I am not certainly not saying that this is strong evidence to do anything different, or that we should change practice based on data that have a p value like this, but it is enough evidence for us to think about the issues, and design further, larger, studies to figure out what we should do with breast milk before giving it to our babies.

Of interest the frequency of severe NEC also looks possibly different between the groups, although again, not ‘significant’ (4 cases with pasteurized milk, 0 with raw milk).  Pasteurizing breast milk, as well as killing pathogens, also will inhibit the growth of good bacteria, so we might really be better off to give raw breast milk, as a source of bifidobacteria and lactobacilli. Or maybe we should give pasteurized donor breast milk with extra probiotics, if the mother can’t provide her own milk.

There is another issue with this study which isn’t fully explained, the authors withheld maternal breast milk if the cultures, of the milk, were positive, which sounds like they were doing routine cultures, and then waiting for the results before giving the milk. They don’t describe their protocol for doing this, and we certainly don’t do that. Maternal milk is not routinely cultured in most units in North America. Some babies in the raw milk group received pasteurized milk when the cultures were persistently positive, which is appropriate as part of their research design, but reduces the power of the study.

This study provides no evidence that pasteurizing mother’s milk is beneficial, and suggests that maybe it is better to use raw milk.

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Extremely Preterm Infants, long term outcomes

A new publication examines in great detail the cognitive outcomes of preterm babies less than 29 weeks gestation. The group from Melbourne, the Victorian Infant Collaborative, has published another study. (Hutchinson EA, De Luca CR, Doyle LW, et al: School-age Outcomes of Extremely Preterm or Extremely Low Birth Weight Children. Pediatrics 2013) I don’t know where Lex Doyle gets the time to do everything that he does, but this study is another from an incredibly productive group that examines the outcomes at about 8 years of age for a population cohort of babies (n=189, 94% of the babies were followed up) that were less than 28 weeks or less than 1000g birth weight, and were born in 1997.

The results are extremely encouraging; the full scale IQ of the extremely preterm infants is about 0.8 SD below the term controls, actual academic achievement is about 0.5 SD worse than the term controls, and there are 15% of the babies classified as having major impairment, compared to 3% of controls. In their results they compare the numerical results, and the proportion of infants with impairments between those who are the most extremely preterm, 23-25 weeks, compared to 26-27  weeks. There are no differences between the subgroups.

As the authors rightly say, the rate of ‘neurobehavioral impairment… remains too high relative to controls’ it may be too high, but it is remarkable how well these babies are doing. Despite missing 17 to 13 weeks of intrauterine brain growth and development, the large majority are functioning well within the normal range. We still need to focus on why that period of being outside of the uterus affects brain development, though it would be very interesting to see in this cohort, what are the outcomes of those that did not get serious neonatal complications. If you take out the babies who had a late-onset infection, NEC or needed surgery, I guess you might end up with a group of babies nearly indistinguishable from the term controls.

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Prepuce wars

A commentary written by a very long list of authors in response to the AAP’s position on circumcision. (Frisch M, Aigrain Y, Barauskas V, et al: Cultural Bias in the AAP’s 2012 Technical Report and Policy Statement on Male Circumcision. Pediatrics 2013). They accuse the task force of the AAP of having a cultural bias, and as a result of having produced a flawed statement. One of their points is that much of the evidence retained is of limited relevance for the practice of routine infant circumcision.

The response of the task force (Circumcision task force: Cultural Bias and Circumcision: The AAP Task Force on Circumcision Responds. Pediatrics 2013, 131(4):801-804.) is to say ‘we’re not culturally biased, its you that are culturally biased’. And we were right.

I think they are all culturally biased, I don’t think its possible not to have biases. We need to recognize them and try to take them into account. I do think that Frisch et al have a point, the prevention of HIV acquisition and AIDS in randomized trials of adults who agreed to be randomized to be circumcised has no relevance at all for routine neonatal circumcision. We have no idea if the same effect would occur with neonatal circumcision, and, of course, the baby doesn’t have a chance to consent. Similarly the data on penile cancer are all observational studies which were all done before HPV vaccination, which is likely to be much more effective and doesn’t require surgery. I don’t think that many adults would consider having a circumcision to reduce the risk of penile cancer (number needed to treat about 200,000), so to use that argument to support routine neonatal circumcision makes little sense.

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Pacifiers (soothers, dummies) are friendly to babies

The baby friendly initiative has been a force for improving breast-feeding rates, with many sensible parts to the program. Unfortunately some of it isn’t evidence based, such as the prohibition of what I will call soothers. I’m originally from England where they are dummies, in the US I  guess a lot of people call them pacifiers,  in much of Canada they are soothers, in Quebec they are ”suces”…. all of which goes to show they have been around a long time, and many cultures have a familiar name for them.

Step 9 of the standards for being called baby friendly states that you must give no soothers to breastfed babies. I don’t know where this ever came from, there is no evidence that soothers have an adverse effect on breast-feeding success. Now there is a study suggesting the opposite, that they are actually beneficial. Kair LR, Kenron D, Etheredge K, Jaffe AC, Phillipi CA: Pacifier Restriction and Exclusive Breastfeeding. Pediatrics 2013. In this before and after study there was a deterioration in exclusive breastfeeding when they instituted a ban on soothers.

There are actually 4 RCTs that have looked at soother use and a systematic review that confirms no beneficial impact on breast-feeding from trying to reduce pacifier use. Of course doing an RCT of this is rather difficult, anyone can easily buy a pacifier or get one as a gift from a helpful relative. The largest trial was Michael Kramer’s PROBIT, done in Belarus. This was a fascinating cluster randomized trial that is still producing results. One of the comparisons was that mothers who received the educational breast-feeding promotion intervention either got extra advice to not use a soother or they got no such advice. The intervention was partially successful, there was quite a bit less pacifier use in the group who got that advice, but that had no effect on the breast-feeding rates. In case you don’t know the trial, it is among the best evidence we have for the benefits of breast-feeding on reduction of intestinal infections, and prevention of atopic eczema. As well as a brand new publication showing no effect on obesity (Martin RM, Patel R, Kramer MS, et al: Effects of promoting longer-term and exclusive breastfeeding on adiposity and insulin-like growth factor-I at age 11.5 years: a randomized trial. JAMA 2013, 309(10):1005-1013)..

This has some importance in neonatology, as we know that soothers decrease pain during minor invasive procedures such as a heel prick, especially when used together with sucrose. So we routinely use soothers with our preterm babies unless the mother doesn’t want us to. That makes it problematic to receive the baby friendly label. Even though we really are friendly to babies! Really, really friendly.

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Weekly Updates #0

I know this is out of sequence, and my weekly updates aren’t in any way weekly, but I thought I’d direct anyone who is interested in keeping an eye on general medical issues to Richard Lehman’s journal review. He is where I got the idea of doing a similar thing for neonatology, he publishes a blog each week in which he reviews the main papers in JAMA, PNEJM, BMJ and the Lancet. He is often very rude about the articles, the motivation of the publishers, and the editor of the Lancet. This week is a typical and sometimes scathing example. I get lost with the new drugs that are being tried and tested in adult medicine, like the etanercept studied in the RCT in the Lancet that he mentions, but some of them seem to be major advances on what was available to me 30 years ago the last time I treated an adult. I’m glad I’m not a general family doctor, keeping up with all this stuff must be tough.

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Not neonatology: Brian Cox again

There is an amazing new series on BBC. Animated by Brian Cox again, called ‘Wonders of Life’. If you can figure out how to get access (within the UK it is available to licence holders, outside of the UK you have to make their servers think you are in the UK. I am not going to tell you how to do that, as it might make me liable for something, but if the initials VPN mean anything to you, you might be able to work out how to do it.)¸In the first episode he talks about (and shows some amazing footage of) an animal that I didn’t know about, a jellyfish that has an intracellular parasite that photosynthesizes. So the jellyfish migrates every day in a reproducible pattern, that leads to the greatest exposure of these parasites to light. They even rotate as they swim so that the largest possible number of parasitic algae are exposed to the light.

We know that one of the crucial steps in the evolution of  eukaryotes was the invasion of prokaryotic cells by parasitic organisms that became mitochondria or chloroplasts. I do not have the biology education that I wish I had, so I did not realize that there are many examples of intracellular parasites, similar to what must have happened a few billion years ago in the early evolution of complex life.

You might ask why a physicist is presenting a biology program. I will let Brian Cox himself explain; so go see the programs, if you can.

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New link in side bar

I don’t play with this blog’s appearance very much, I don’t have enough time to fiddle about. But I have just added a new link to the side-bar. A link to a very young foundation, the Canadian Premature Babies Foundation. If you follow the link, you may see a familiar image, in colour this time, of a famous little girls hand, with my wedding ring around the wrist.

This new foundation has my full support, including, but not limited to, the use of the image. If you look at the ‘about us’ page you will see why. The purpose and goals of the foundation are very much in line with what I think we need to do. You can also view a few youtube videos (link here) related to the work of the foundation, including one in English and one in French from the president of the foundation Katharina Staub.

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Weekly updates #26

Richburg DA, Kim JH: Real-time bowel ultrasound to characterize intestinal motility in the preterm neonate. J Perinatol 2013. You can quantify intestinal motility with bed-side ultrasound. Neat. Now we need to know what to do with the information, sounds like Jae Kim is already looking into that.

Boss RD, Urban A, Barnett MD, Arnold RM: Neonatal critical care communication (nc3): Training nicu physicians and nurse practitioners. J Perinatol 2013. This is addressing a real need, how to teach neonatal health care providers to talk to parents. It sounds like they have a good system, the trainees felt more comfortable, and used the skills taught frequently. What we don’t know is whether the parents were better informed, felt more comfortable etc.

Cremer M, Weimann A, Szekessy D, Hammer H, Buhrer C, Dame C: Low immature platelet fraction suggests decreased megakaryopoiesis in neonates with sepsis or necrotizing enterocolitis. J Perinatol 2013. So where do the platelets go to? It happens quite often that the platelet count gets very low during sepsis or NEC, this study suggests that they aren’t being consumed, rather, usually they are not being produced. I don’t know if my lab can measure this feature of the platelets, it sounds a bit complex, but then most of what they do in the lab sounds complex to me.

Slaughter JL, Stenger MR, Reagan PB: Variation in the use of diuretic therapy for infants with bronchopulmonary dysplasia. Pediatrics 2013. This database study looks at diuretic use in infants with BPD. There are enormous differences, ranging from a hospital that gives about 62% of the babies occasional short courses of less than 5 days, but rarely gives more than 5 days, to one hospital where over 80% of the babies get both long and short courses. I guess as usual that means we need some good data.

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Losing a twin

Vasilescu C, Garel M, Caeymaex L: [experience of parents after the loss of a newborn twin in the nicu: A qualitative study 3 years after the death.]. Archives de pediatrie. 2013(0). This is a nice qualitative study, with a reasonable sample size of 26 parents, (15 mothers and 11 fathers) who lost a twin in the NICU, while the other survived. How do they live that experience? The article is in French, and I think it is probably unique in the literature. I am sometimes a bit cynical about qualitative studies, but this is the type of thing that you can’t do any other way, and which can be really important.

I reproduce the final conclusions below, with a translation beneath that if you don’t parler.

Entre la perte d’un singleton et d’un enfant jumeau, la question n’est pas la différence d’intensité de la tristesse des parents, mais plutôt la coexistence de sentiments très
forts : joie et tristesse, espoir et désespoir, investissement et détachement. Pendant l’hospitalisation et au cours d’un suivi ultérieur, les soignants doivent pouvoir entendre les
parents évoquer ces sentiments contradictoires qui les assaillent. On peut alors espérer que les parents se sentent soutenus dans le processus qui leur permet d’intégrer la
perte, d’investir l’enfant en vie, de faire en sorte que les représentations des enfants s’emmêlent le moins possible et que dans l’histoire familiale, la place de chaque enfant
soit préservéeé.

”Between the loss of a singleton and of a twin, the question is not the difference in intensity of the parents grief, but rather the co-existence of very strong emotions: joy and sadness, hope and despair, investment and detachment. During the hospitalization and subsequent follow up, carers must be able to listen to the parents expressing these contradictory feelings. It is to be hoped that the parents feel supported in a process which allows them to come to terms with their loss, to invest in the living child, to find a way that the images of the two infants become confused as little as possible, and that in the story of the family the place of each child is preserved.”

There aren’t many studies of what happens to parents after a neonatal death, but Dr Caeymaex has been publishing in this area. It is understandably a little tricky to do this kind of research, but it can really help us to find out how to give the best care to families. One of the groups previous publications was in PLoS one, which is nice because it is free access, but unfortunately, probably didn’t get the attention it deserved, as not many people I know read PLos one (I don’t either!). This is one of the very few times that parents have been followed after an end-of life decision was made. That one is in English, Caeymaex L, Speranza M, Vasilescu C, Danan C, Bourrat MM, Garel M, Jousselme C: Living with a crucial decision: A qualitative study of parental narratives three years after the loss of their newborn in the nicu. PLoS One 2011, 6(12):e28633. It gives some guidance based on the parent interviews:

‘The physicians’ attitudes that were perceived as helpful in the long term were explicit sharing of responsibility, clear expression of staff preferences, and respectful care and language toward the child.’

I am against a one size fits all approach, but I think those sort of general guidelines are indeed generally applicable. The clear expression of staff preferences I think needs some modulation, to avoid being coercive, once you say that ‘everybody here thinks that we should do A’, then that leaves little room for the parents values to be expressed.

The interpretation section of the abstract is nicely put: ‘Parents find it valuable to express their opinion in the end-of-life decision making process of their child. Nonetheless, they do need continuous emotional support and an explicit share of the responsibility for the decision. As involvement preferences and associated feelings can vary, parents should be able to decide what role they want to play. However, our study suggests that fully autonomous decisions should be misadvised in these types of tragic choices’

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Oh No; not renal dose dopamine again!

This is the sort of thing that really irritates me: If you report ‘we did X, and Y happened’ the obvious question should be, ‘what would have happened if you didn’t do X?’

That is called having controls! It is the basis of all science! I am using too many exclamation marks!

So if you take normotensive preterm infants with a low urine output, and give them low dose dopamine, the urine output increases. SO WHAT! (exclamation marks and all capitals, not good scientific blogging technique, but I am a bit irritated by this publication)

(Crouchley JL, Smith PB, Cotten CM, Hornik CD, Goldberg RN, Foreman JW, et al. Effects of low-dose dopamine on urine output in normotensive very low birth weight neonates. J Perinatol. 2013)

I can tell you from simple first principles of common sense, that if you take normotensive preterm infants with  low urine output and DON’T give them dopamine, then their urine output increases! If you further analyze the data, then the lower the urine output before not giving dopamine, the greater the increase when you don’t give them dopamine.  That is called regression to the mean.

I think there are many good reasons to report case series, and there are many things we can learn from them, but to report something that we already know is done without good supporting evidence, that has been proven ineffective in older patients in randomized trials, that has no good physiological evidence to support it, helps no one.

To recap those points, there are systematic reviews in pediatrics and in adult intensive care that show no evidence of renal protection from low dose dopamine infusion. There are multiple studies in neonatal mammals which show that the renal vascular dopamine receptors are present, but stimulating them has no effect in the perinatal period. Dopamine receptors (and there are many) are G-Protein linked receptors, and it appears that the renal vasodilatation that you can get from dopamine stimulation of these receptors is absent in the neonatal period, even though the receptors are present (at term at least, probably) and the G proteins are present, the link between them appears to be inactive. Even when it is present, as in healthy older patients and adults, there is no evidence that stimulating the dopamine receptor produces clinical benefit in the critically ill.

On the other hand we know that low-dose dopamine suppresses the pituitary, and specifically the production of TSH, so the longer you give dopamine, the lower the activity of the thyroid. Prolactin, in addition (even though I don’t know how important it is in a newborn infant), is completely suppressed by dopamine administration.

Dopamine also depresses respiratory drive. Dopamine receptors in the carotid body, when stimulated by dopamine, decrease their output which projects on respiratory control centers. So you can induce apnea in newborn lambs when you give them dopamine. (Don’t try and find that in the literature, I did the study in the lab of Jim Fewell in Calgary when I was a new staff in Edmonton, but I never published it, to my shame. It was quite dramatic, when I started the dopamine the lambs immediately stopped breathing, and then after a long pause started breathing periodically, within a few seconds of stopping the dopamine infusion they started breathing regularly again). Other data which is actually published also shows the respiratory depression with dopamine.

If someone wants to show whether there is an effect of low dose dopamine on urine output, you have to have controls! And in fact is has been done… Cuevas et al published in 1991 one of the very few studies of a catecholamine compared to no treatment. In a small study with 3 groups, they showed that with no dopamine urine output increased  to 4.8 mL/kg/h. With either of the 2 doses of dopamine that they used the urine output increased less! (to 3.8 mL/kg/h with 1 mcg/kg/min, and to 3.2 with 2.5 mcg/kg/min).

The only thing which they report as being significant was that the lower dose group, but not the higher dose, had higher fractional excretion of sodium, but as they used uncorrected t-tests to compare the data in the 3 groups, and they compared 7 different renal variables at 3 time points, it is hardly surprising that something was ‘significant’.

To re-iterate there is no evidence that low dose dopamine has any beneficial effects, neither on the kidney nor on other organs, and this new publication does not change that.

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