Probiotics: what do parents want?

Some day, I might slow down with the probiotics posts, but not right now!

A letter published in Archives reports the results of a parent survey. In the 3 NICUs implicated probiotics are given with parental information and an ‘opt-out’ approach, where probiotic administration is routine, but parents can refuse if they wish.

Parents of babies recently in these NICUs were surveyed,

the vast majority of respondents (51/53; 96%) considered that parents of high-risk premature babies born at other units that do not yet offer probiotics should have the right to be informed of the evidence of their potential benefits. Most (34/53; 64%) also felt that, given the current evidence on risk reduction for NEC or death, other parents deserved the right to be informed of the data and the option of probiotic treatment for their babies.

They also note

 Only 7/58 (12%) units gave probiotics to preterm/VLBW babies; 11/58 (19%) units stated they were considering whether to introduce probiotics and 22/58 (38%) units reported that they were awaiting results of the Probiotic in Preterm babies Study.

and not surprisingly

We find that parents focus on the short-term outcomes of survival and avoiding NEC rather than on any theoretical longer-term effects such as on immune function or metabolism. While doctors debate and deliberate, parents would appear to prefer probiotic proactivity.

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Neonatal Updates: more nutrition

It is not surprising when I write a blog post about nutrition in the preterm neonate to find that at least one, and on this occasion two, of the articles are from the productive pen of Johannes van Goudoever.

Vlaardingerbroek H, Vermeulen MJ, Carnielli VP, Vaz FM, van den Akker CHP, van Goudoever JB: Growth and fatty acid profiles of vlbw infants receiving a multicomponent lipid emulsion from birth. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):417-427.

SMOFLipid is a new-ish lipid emulsion which is made from several different sources, and as as result contains omega-3 fatty acids, as well as omega-6. It has been approved in Canada for TPN in adults, and has been approved in Europe also for neonates. Which I find a bit surprising as we had a recent presentation from our pharmacy, and the total published data from several small trials came to about 100 treated preterm babies, and 100 controls.

The NICU team in Rotterdam now add to that data, they have performed a clinical RCT comparing clinical outcomes among infants randomized to either SMOFLipid or Intralipid. 96 VLBW babies were randomized within 6 hours of birth, starting at 2 g/kg/d on day 1, and 3 g/kg/d on day 2.

The growth on SMOFLipid was improved, and the fatty acid profile was also improved with the DHA and EPA levels being maintained and significantly higher than the controls. There were no adverse effects noted. There were fewer cases of late onset sepsis, 27% rather than 40% had this complication. This is not individually significant, but some of the same authors have previously published a meta-analysis, which showed a 25% reduction in LOS based on 2 small trials and barely significant. If you add the new numbers to the data already in the literature, which which they do in their discussion, you now have a reduction in sepsis of 28% and the upper limit of the 95% CI is 0.94. So a very interesting finding, for which there is some theoretical/basic science support, which needs to be replicated in further larger trials.

I think there is good theoretical justification for using an emulsion which includes omega-3 fatty acids, and if we were to design the first ever intravenous lipid for a trial today we would probably have something like SMOFLipid in mind. However, I think we really should demand robust efficacy and safety data in comparison to the current standard before changing over. Even with the knowledge that when intralipid was introduced for preterm babies there was really no good controlled evaluation. I don’t think there is a single RCT against placebo of intralipid as a component of TPN in preterm infants, which is not that unusual for things that were introduced in the 50′s and 60′s. What to do about that is not entirely clear to me, but I don’t think the answer is to switch to a newer therapy after a few very small RCT’s. I think the time is now to ensure that we have big simple RCTs comparing current usual care to any innovation, even is the current usual care is based on very little, or almost no, data.

Olsen IE, Harris CL, Lawson ML, Berseth CL: Higher protein intake improves length, not weight, z scores in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):409-416.This secondary analysis of data from a trial of a concentrated liquid human milk fortifier shows that there was a correlation between higher protein intakes and better length at 28 days.

Christmann V, de Grauw AM, Visser R, Matthijsse RP, van Goudoever JB, van Heijst AFJ: Early postnatal calcium and phosphorus metabolism in preterm infants. Journal of Pediatric Gastroenterology & Nutrition 2014, 58(4):398-403. How much calcium and phosphorus should we supply, and what should be the ratio between them? The answers to these questions are still not entirely clear to me. Avoiding early hypocalcemia, and/or hypophosphatemia, and then ensuring later good bone mineralisation may need different answers to those questions. The data in this study supports the idea that you need a lower calcium/phosphate ratio in the first couple of days, and that gradually changes afterward.

An accompanying editorial gives some guidance, much of which needs confirmation in other studies.

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Zinc supplementation: should we be galvanized into action?

I wasn’t sure how many non native-English speakers would get that joke, and jokes are rarely improved by explaining them, so if you don’t get it, just keep on reading.

Terrin G, Berni Canani R, Passariello A, Messina F, Conti MG, Caoci S, Smaldore A, Bertino E, De Curtis M: Zinc supplementation reduces morbidity and mortality in very-low-birth-weight preterm neonates: A hospital-based randomized, placebo-controlled trial in an industrialized country. The American journal of clinical nutrition 2013, 98(6):1468-1474. A multi-center RCT enrolled nearly 200 VLBW infants at 7 days of age to receive a zinc supplement (intravenous and oral) or placebo. The zinc supplement gave much more than the current recommendations, around 10 mg per day, while the controls received around 1.3 mg/day, which is consistent with some guidelines, but a bit less than some newer guidelines (which recommend about 2-2.2 mg/kg/d). The authors were interested in clinical outcomes, as zinc has multiple actions, being incorporated into several enzymes, and having effects on immune function and maybe cerebral development. The zinc supplemented group had no cases of NEC (compared to 6% in the controls), but a few more cases of late-onset sepsis; they had less PVL, slightly less BPD and no RoP >stage 2 (compared to 3% in controls). The primary outcome of the study was a composite including the development of at least one of those complications, which was significantly reduced by zinc supplementation, 27% vs 42%. There were quite a few deaths in the study after enrollment, and I think the authors should have included mortality in their composite outcome. There were, however, more deaths in the controls, 17/96 vs 5/97, which was also significant, and I assume that a combined outcome of death or morbidity would have been significant.

An editorial accompanying the article gives some interesting background, and notes that zinc reduces copper absorption, and when high doses of zinc are given, also inhibits iron absorption. It is appropriately cautious, and states that we should be ensuring that babies receive zinc according to current recommendations, and that further research on higher, ‘pharmacologic’ doses of zinc will be important.

As far as I can work out, current human milk fortifiers added to human milk don’t seem to give enough zinc, they add about 0.72 to 1.2 mg of zinc per 100 mL of milk, depending on which you use, it appears that we should probably be giving more, just based on balance studies.

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Bugs and Breast Milk

Neonatology recently published a commentary asking the following question about routine probiotic supplementation, ‘what will it take to change practice?

This was immediately followed by another commentary, from Neena Modi, explaining why she is still reluctant. Although I have a great deal of respect for Neena, I must say, on this issue, she is wrong.

She reports her unit’s use of fresh colostrum, and the extensive use of fresh breast milk. Now at the risk of receiving howls of protest from the breast milk police (I am one of them myself!) there are stronger data for the efficacy of probiotics than for fresh breast milk, when it comes to prevention of NEC. Indeed one of the mechanisms for the activity of breast milk is probably the frequent ‘contamination’ of breast milk with probiotic organisms, as she mentions herself. I certainly agree that there are also theoretical advantages of other components breast milk, such as the fucosylated oligosaccharides, lactoferrin, and lysozyme. Also secretory antibodies (Rogier EW, et al: Secretory antibodies in breast milk promote long-term intestinal homeostasis by regulating the gut microbiota and host gene expression. PNAS 2014 a new study in a mouse model showing the probably beneficial effects of sIgA on promotion of a normal microbiome).

One place where I disagree with her are the examples she uses that ‘some therapies initially embraced enthusiastically and widely believed to be safe – for example routine oxygen administration at resuscitation, and antenatal antibiotics for women in spontaneous preterm labour with intact membranes – were ultimately shown to be of no benefit or to have harmful long-term consequences’. As I pointed out during my recent presentation in Scottsdale (which you can download if you wish), therapies which fall into that category have a common feature, that they were adopted without much, or without any, evidence from randomized controlled trials. They were adopted based on ‘expert opinion’ or, more commonly, based on fashion.

Which is actually the opposite of what we see with probiotics. In this instance we have extensive evidence from RCTs, of efficacy and of safety, and yet they have not been ‘embraced enthusiastically’.

As mentioned, breast milk contains probiotic organisms, so if you use fresh breast milk you are usually giving probiotics anyway, you won’t be giving very many in the first few days, and you have no idea which strains you are administering. There are also, of course, frequently pathogens in breast milk, and mothers who have received antibiotics have a very different microbiome of their breast milk.  A new review article (Latuga MS, Stuebe A, Seed PC: A review of the source and function of microbiota in breast milk. Semin Reprod Med 2014, 32(1):68-73) is a fairly brief read, and summarizes the data about the germs that are commonly in breast milk, and how they get there, including the idea of entero-mammary trafficking, meaning that they might be specifically transported to the breast tissue from the GI tract.

In a new study published on-line in JPGEN the frequency of finding lactobacilli and bifidobacteria in breast milk was lower than in some other studies, and importantly was substantially decreased by giving antibiotics to the woman. (Soto A, Martin V, Jimenez E, Mader I, Rodriguez JM, Fernandez L: Lactobacilli and bifidobacteria in human breast milk: Influence of antibiotherapy and other host and clinical factors. Journal of pediatric gastroenterology and nutrition 2014). Many mothers who deliver extremely preterm have received antibiotics, this study demonstrates, as we would suspect, that the women who received antibiotics had much lower probiotic counts in their breast milk.

And finally another study showing that antibiotics given to preterm infants do actually kill probiotic organisms, promote the growth of resistant pathogens, and increase the later risk of NEC. (Greenwood C, et al: Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of enterobacter. Journal of Pediatrics 2014).

So if you give breast milk to very preterm infants, you administer an unreliable source of the same organisms as if you actually give a probiotic preparation. You may not give any probiotics if the mother received antibiotics, and if the baby is on antibiotics you really screw up their intestinal microbiome and kill any good bugs that they are getting from the breast milk.

The best way to be certain that the baby receives a source of these protective organisms is by giving them a verified source of probiotics, which will decrease the rate of NEC, even among babies with a high rate of breast feeding.

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Single baby rooms?

Terrie Inder and her colleagues have put the cat among the pigeons (as we say in England, I guess we are not keen on pigeons).

Her (non-randomized) study suggests that babies who were treated in single rooms had poorer language skills than babies treated in a more traditional unit, with large, multi-patient rooms. Depending on bed availability infants were either admitted to large rooms of 8 beds or so, or single rooms. They followed the babies under 30 weeks gestation out to 2 years of corrected age, 83% of the survivors (n=86) returned for neuro-developmental follow up. I won’t mention the EEG and imaging findings which showed some differences, but rather the 2 year Bayley scores, which were worse in the language domain for babies from single rooms, and motor scores were also somewhat worse.

Single room designs have become the norm for new NICU construction based on data which show an increase in parent satisfaction, an increase in parental presence, and expected reductions in health care associate infections, especially a reduction in patient to patient spread of viral diseases.

This new data should make us reconsider carefully how to optimise the neonatal environment.

One of the possible explanations for this finding is that single rooms tend to be very quiet, and they may be too quiet, with not enough auditory stimulation for the development of the auditory pathways. But perhaps this is not generalisable, in the USA maternity leave is usually 1 month without pay. As I understand it, this may vary by state, but if you have a long stay baby in the NICU, being with the baby a few hours every day and talking to them is extremely difficult to sustain unless you are independently wealthy, or unemployed.

In the NICU where these new data come from, parental visiting was an average of 2 hours a day in the open rooms, and 4 hours a day in the single rooms (in the 3rd and 4th week of hospitalisation). This major increase in visiting time may not be enough to counter the 20 hours of very quiet, undisturbed rest, which we usually think of as a benefit.

In other cultures, mothers are able to spend much longer. Parents in Québec can share a year of parental leave, and for the first half of that can qualify for income from a government supported insurance scheme. It may be that in cultures where the parental leaves are more generous, parents will spend longer with their babies in single room designs, that would be interesting to see.

A commentary in Acta Paediatrica is written by one of the investigators of the Stockholm RCT of Family Centered Care. In that study infants stable enough for intermediate care were randomized, one part of the family care intervention was a single room. I can’t see from that report how long the parents stayed with their infants, and there was no long term follow up.

The thoughtful commentary (Örtenstrand A. The role of single-patient neonatal intensive care unit rooms for preterm infants. Acta Paediatrica. 2014;103(5):462-3) refers to a systematic review that I was not aware of. The SR includes 10 articles, only one of which, the Stockholm study, was an RCT. The others are various observational designs with potential biases, but which suggest a range of benefits of single rooms.

I think it is possible that the effect shown in the study from St Louis is a real effect. I would be a little surprised if the single room was actually quieter than being in utero, so I would guess that it is the nature, rather than the intensity, of the sounds that may be important.

Which brings me back to the issue of the mother’s voice, and the importance of the mother speaking to her baby. Babies born at term recognize certain features of their mother’s voice from very early after their birth, almost certainly because the antenatal experience of the mother’s voice has impacts on the development of central auditory processing. I think this suggests that the potential adverse effects of being in a single room might have to do with reduced exposure to voices, and that maybe we can counter this effect by encouraging mothers to talk to their infants whenever they are present, and to use recordings of the mothers’ voices when they can’t be there.

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Presentation in Scottsdale AZ

For anyone who was at the AAP workshop in Scottsdale, and anyone else who might be interested. I have put the powerpoint presentation on this blog, under ‘Presentations from our group’ the first heading is AAP Scottsdale AZ 2014. If you click on that you will find the powerpoint. Feel free to download and use any slide that you think is useful to you.

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Do preterm babies need their thyroid?

Now I am very confused. I thought I knew that many very preterm babies had low serum thyroxine levels (this study confirms that). It seems to be a variant of sick euthyroid syndrome, levels tend to fall for about the first week of life then start to increase again. I thought it was well established that infants with a low thyroxine had poorer outcomes, in terms of long term impairments. To my mind it was not clear whether this association was causative, and randomized replacement trials have been generally negative, with no benefit demonstrated, but further appropriate trials were warranted.

Now a new study (Scratch SE, Hunt RW, Thompson DK, Ahmadzai ZM, Doyle LW, Inder TE, et al. Free Thyroxine Levels After Very Preterm Birth and Neurodevelopmental Outcomes at Age 7 Years. Pediatrics. 2014) suggests the opposite.  In this group of babies, from the incredibly productive group in Melbourne, those babies that had higher thyroxine levels had worse outcomes. The main difference between this study and the previous ones is that the infants were studied at 7 years, so such things as language development can be examined in more detail. The babies were probably less sick than in some of the older studies, as very preterm babies are generally less sick than they used to be, and many of the older studies had less antenatal steroid use, and no surfactant. But I am still a bit confused by the reversal of the finding.

The authors note that recent models suggest that the sick euthyroid syndrome may well be adaptive and beneficial, rather than dangerous. If this is true, and higher T4 is a sign of poorer adaptation, then why the older studies showed the contrary remains a puzzle.

The authors also note that the method they used those several years ago to measure T4 is no longer considered optimal (and may be affected by low serum proteins which are common in the preterm). It would be interesting to have a new study, using the best modern assays, with cohorts from Australia, where high T4 seems to be bad for you, and from the US and Holland where low T4 seems to be the problem!


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