Predicting Outcomes?

A new publication and an editorial address some of the issues around whether we can predict outcomes in preterm infants.

This was a large cohort study from the NICHD network, the usual multi-multi-multi-author paper, 34 authors wrote this paper apparently,  Hintz SR et al: Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants. Pediatrics 2014. There were 480 infants of less than 28 weeks who were enrolled in the SUPPORT trial (from 16 of the 20 SUPPORT centers), they had early head ultrasounds, late head ultrasound near term, and MRIs close to term. Then followed up with standardized neurodevelopmental testing. 10% had major anomalies on early ultrasound, 6% on late ultrasound. 20% had MRI white matter injury defined as moderate or severe, and 16% had cerebellar lesions seen on MRI.

The authors showed that if you have imaging brain abnormalities you are more likely to have adverse outcomes. There are many p-values less than 0.001.

Which is hardly surprising.

They show that early head ultrasounds are of little value when you take into account clinical factors and late findings. They also show that

 a substantial proportion of children with adverse late Cerebral US or MRI findings in our cohort did not have severe adverse outcomes at 18 to 22 months, emphasizing that neuroimaging must not be used in isolation to predict outcomes.

To me this is the most important finding of this study.

But first lets look at early ultrasound findings: of those without a major finding on a 4 to 14 day ultrasound, there were 6% with “neurodevelopmental impairment”; of those with a serious hemorrhage or cystic PVL there were 28%. If we make that a ‘glass half-full’ statement, that means that if you have serious early ultrasound findings there is a 72% probability that you will not have “impairment”.

Late imaging findings were more strongly associated with “impairment”, but only the 18 babies who had severe MRI white matter injury were really any different in terms of outcomes  (the babies with moderate abnormalities don’t seem much different to those with ‘normal MRI’), and among those babies, half had serious cerebral palsy and 22% had Bayley 3 cognitive scores below 70, (in other words, 78% of infants with severe white matter abnormality on late MRI did not have low cognitive scores on Bayley 3 testing).

The positive predictive value of cerbellar lesions was also very poor, 10% of infants with cerebellar lesions had moderate to severe cerebral palsy, and 15% had cognitive scores below 70.

Late head ultrasounds, (scored as abnormal in the presence of a shunt, moderate to severe ventricular enlargement, cystic PVL or a porencephalic cyst), were to my eyes, just about as good (or bad) as an MRI; with PPVs ranging from 23 to 50%.

What does all this mean in clinical practice? I think we should, as the authors of this study state “re-evaluate the practice of early head imaging” in very preterm infants. I think the data also suggest that we should “re-evaluate the practice of late head imaging”! We should continue to examine closely why we are doing such studies, what we want to get out of them, and how we inform parents, both for prior consent and after we have the result.

An editorial accompanying the study asks many of the same questions, as Eric Eichenwald states, “we need to understand the potential impact of of our predictive uncertainty on the parents of these vulnerable infants. …neuroimaging techniques.. cannot yet be used to determine follow-up strategies or target interventions after discharge and thus may be of little or no benefit to many parents.” (and he references the article by Annie and me!)

I think an objective evaluation of the usefulness of these tests for predicting outcomes in individual babies would lead to the inescapable conclusion that they are close to useless. Sometimes worse than useless, as they give false reassurance, or create false anxieties.

Both early and late head imaging fail to satisfy any of the criteria for a useful screening test. We should consider limiting early head ultrsound to use for detection of treatable lesions, and later imaging for research purposes only, with extensive informed consent to ensure that parents are well aware of the limitations of both MRI and near term head ultrasound.

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Not neonatology: le grand tour

We have decided as a family to take a break, a pseudo-sabbatical to visit the down-unders, learn about their culture, present at conferences, and generally focus on de-stressing and self-improvement. The 3 kids are out of school, and will be getting intensively tutored by Annie and me.

People’s reponses have been universally positive, including our colleagues in Sainte Justine, and the children’s teachers. So far no-one has said ‘but what about the kids missing 3 months of school?’

Tuesday, on our trip down here we had an 8 hour break in San Francisco, so we decided to go to the California Academy of Sciences, as recounted in the blogs that the kids have set up to keep in touch with their class mates: Axel’s blog is tentacules and Violette’s is simply Violette’s blog: even Tai is guest posting on Axel’s blog!

Then on to the antipodes for our 3 month break in the sun, or so we thought… so far New Zealand and sun seem to be antonyms. The countryside is beautiful, and the birds are noisy, but the rain has been almost constant.

Since our arrival in Auckland we have been exploring a little, we have seen most of the indoor attractions of Auckland, which fortunately has an interesting Museum and Art Gallery, and even an indoor mini-golf! we have had a couple of days without rain, just cloudy skies, the first we went walking among the tree ferns at Hunua ranges. The tree ferns are beautiful, and many are unique to New Zealand, this specimen was over 10 metres tall, with epiphytic bromeliads growing from the trunk.

treefern

Close to the car park this pool with waterfall

falls

Another day we climbed a volcano, Rangitoto island in Auckland bay is a volcano that erupted about 600 years ago. I don’t fully understand the lush vegetation, I thought it took longer than that to create good soil from new volcanic rock. This is a view of Auckland from Rangitoto, showing a typical cloudy sky, looking over the lava poking out of the water and the mangroves.

Auckland from Rangitoto

The Auckland museum has a reconstructed Maori dwelling, with this couple as the base of one of the door supports.

Maori figures

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Lactoferrin and the bowel

There’s a lot of activity in Lactoferrin research recently, this protein is very promising as prophylaxis against infections and perhaps also against necrotising enterocolitis.

First of all a study giving bovine lactoferrin to newborn piglets which showed a stimulatory effect on crypt cells in the developing intestine. Reznikov EA, Comstock SS, Yi C, Contractor N, Donovan SM: Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets. J Nutr 2014, 144(9):1401-1408. Exactly which cell type isn’t clear to me, but Paneth cells in the crypt have been suggested to be important in the pathophysiology of NEC. (McElroy SJ, Underwood MA, Sherman MP: Paneth Cells and Necrotizing Enterocolitis: A Novel Hypothesis for Disease Pathogenesis. Neonatology 2013, 103(1):10-20).

Another study from the same group, in the same model (in fact I think it is the same piglets) Comstock SS, Reznikov EA, Contractor N, Donovan SM: Dietary Bovine Lactoferrin Alters Mucosal and Systemic Immune Cell Responses in Neonatal Piglets. The Journal of Nutrition 2014, 144(4):525-532. Both spleen cells and mesenteric lymph node cells showed signs of enhanced immune responses with dietary bovine lactoferrin.

Colostrum, and mature breast milk contain significant amounts of lactoferrin. (in fact the piglets in the previous study were deprived of sow colostrum in order to do the study). Breast milk is almost always colonized with bacteria, very often bifidobacteria are present, and often lactobacilli also. In this study, which included both full term (34) and preterm (14) mother infant (human) pairs, the lactoferrin concentrations were similar to previous data, with around 7 mg/mL in colostrum dropping to 2.3 in mature milk, similar in term and preterm subjects. Mastromarino P, Capobianco D, Campagna G, Laforgia N, Drimaco P, Dileone A, Baldassarre ME: Correlation between lactoferrin and beneficial microbiota in breast milk and infant’s feces. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(5):1077-1086. They also showed bacterial DNA of lactobacilli in all of the breast milk, and bifidobacteria in all but one of the breast milk samples, with a higher concentration of lactobacilli in the preterm milk, and similar bifidobacteria concentrations. They also analyzed stool samples, and were able to find lactoferrin in the stools, and found lactobacilli and bifidobacteria in almost all the stools also.

The next study examined the effects of heat-treatment and ultraviolet light on the lactoferrin concentration of colostrum (also on what they call hospital milk, which is milk supplied by sick cows which cannot be sold, and may be contaminated with many bacteria). The heat treatment was to 63 degrees for 60 minutes, which is similar to many human milk bank standards I believe. Lactoferrin was measured by an ELISA, and I don’t know whether lactoferricin, or other active or potentially active parts of the molecule would react with the assay. Teixeira AGV, Bicalho MLS, Machado VS, Oikonomou G, Kacar C, Foditsch C, Young R, Knauer WA, Nydam DV, Bicalho RC: Heat and ultraviolet light treatment of colostrum and hospital milk: Effects on colostrum and hospital milk characteristics and calf health and growth parameters. The Veterinary Journal 2013, 197(2):175-181. The study shows a number of things : cows’ milk colostrum has much less lactoferrin than human (which was already known), about 0.3 mg/mL falling to around 0.2 in mature milk. Both heat treatment and ultraviolet treatment reduced the lactoferrin concentrations, and also the IgG concentrations. It’s interesting sometimes to read research form other fields in some detail, this study was performed in a farm which has 2800 cows, and they randomized over 280 animals into the 3 groups. They calculate the sample size based on daily weight gain, which is therefore the primary outcome variable, but they don’t use the term, and report that outcome in very little detail, right at the end of the results.

Also interestingly, low birth weight calves are at higher risk of infection than normal birth weight, being LCBW (low calf birth weight) less than 37 kg is associated with much more diarrhoea, and they also had lower serum IgG concentrations.

Part of the efficacy of lactoferrin may be that it sequesters iron, so that it is no longer available for organisms that rely on iron to replicate, such as E Coli (although there are several other mechanisms also). If you then add more iron to the feed, does this overcome the benefits? A number of in vitro studies have had variable results, the latest took colostrum from mothers delivering at term, and tested bacterial growth effects of the milk with and without the addition of a human milk fortifier, used for preterm infants, that contains iron. They found no effect of the iron on Pseudomonas or Staph Aureus, but E Coli grew a little more actively when the fortifier with iron was used. Apparently other studies have had different effects, such as showing a direct bacteriostatic effect of breast milk, and showing more adverse effects of the iron. Campos LF, Repka JCD, Falcão MC: Effects of human milk fortifier with iron on the bacteriostatic properties of breast milk. Jornal de Pediatria 2013, 89(4):394-399.

Of course iron is also important as a catalyst for the production of reactive oxygen species, so another potential benefit of lactoferrin may be to reduce free iron, and therefore to reduce potential oxidative injury of the gut. This is suggested by the results of another study: Jegasothy H, Weerakkody R, Selby-Pham S, Bennett LE: In vitro heme and non-heme iron capture from hemoglobin, myoglobin and ferritin by bovine lactoferrin and implications for suppression of reactive oxygen species in vivo. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 2014, 27(6):1371-1382.

Finally a review article which discusses the potential benefit of lactoferrin supplementation. Michael Sherman, who has studied lactoferrin, including recombinant human lactoferrin relates the importance of ensuring that preterm babies get colostrum. Which I certainly agree with. The authors also state however that there is no lactoferrin preparation proved by the FDA for use in preterm infants, which is of course true, but they state in the abstract ‘regulatory burdens required to bring lactoferrin to the bedside may limit its availability’. When the list of trials completed and in progress at the end of the article are examined, I hope that is not true. If the data are confirmatory, we should have plenty of good data to be able to obtain approval. Sherman M, Miller M, Sherman J, Niklas V: Lactoferrin and necrotizing enterocolitis. Current Opinion in Pediatrics 2014, 26(2):146-150.

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The Power of Parent’s Touch.

My friend and colleague Marsha Campbell-Yeo is part of the Centre for Pediatric Pain research. She has just produced a video about controlling pain in young babies, which you can see here:

My only beef is that all the parents shown actually doing any skin-to-skin are mothers. Now we can’t breast feed, and maybe our kangaroo care isn’t as effective as mothers’ (one of Martha’s research studies), but we fathers can still help!

UPDATE: actually Marsha points out that there is a father doing skin to skin; my mistake. ***

They have previously made a video about pain control for ‘shots and needles’

 

and have a number of other resources available on their website.

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More about Preemie Voices

For those of you who might be interested in buying the book that I blogged about a few days ago, please note that you can get the book at a big discount, by contacting Saroj directly, using the link on her website.

Also, now I have had the chance to look at the book a bit more, there are sections after the former preterm babies stories that are very interesting, including several chapters written by Saroj about outcomes of very preterm babies, about how her ideas of quality of life etc have developed, and about impacts of prematurity on families. Also there is a great chapter by her long time collaborator Peter Rosenbaum. He reflects on views of disability and how our appreciation of impairments and the way they impact on individuals have changed over the last half century. Well worth reading, in addition to the ‘preemies’ voices’ stories and Saroj’s chapters.

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Toxic exposures in the NICU

I thought I’d blog about this article for two reasons.

Firstly, it points out the theoretical exposure to phthalates in patients in the NICU, which are enormous and potentially with multiple toxic effects. Exposures could possibly be as high as 160,000 times the limits of intakes that we really want for our babies, and this might lead to serious adverse effects. Those toxic effects include hepatic effects, adverse pulmonary impacts and reproductive (especially male) toxicities. Of course all those words, ‘possibly’ ‘theoretical’ ‘might’ are caveats that require investigation and more solid evidence, and also some assurance that alternatives are better. We need to be sure that alternative polymers that don’t require phthalate plasticizers are also safe, but if we can be reasonably sure it seems that it would be a good idea to make the change.

The second reason that I am writing this post is that I wanted to try out the new feature of the Nature group journals. I can now include a link so that anyone who follows it will be able to read the full text article if they wish. So give it a try, and, if it works, then, even if your institution does not have access to the Journal of Perinatology, or if you read from home, then you should be able to see the whole article. You won’t be able to download or print it, but having permanent access to the articles on-line will be helpful for many.

Here is the link:

http://rdcu.be/bKwS

 

 

 

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Listening to the voices of Preemies

Or rather the voices of adults who were born very preterm. Saroj Saigal is well known to many of us in neonatology, either by reputation, or, for the lucky ones among us, as a friend.

Her insights into quality of life, what it means to our patients, and how patients evaluate their own quality of life, have been extremely influential, and have had a great impact on how we practice, and how we talk to parents. Her studies of adaptation to adult life among former very preterm babies were also eye-opening, and showed how well her cohort was doing as they entered adulthood.

Her latest innovation is to gather the stories of former preterm babies, now they are adults, and publish them as a book. You can buy her book from a number of places, just follow the links under the bookstore tab on her web-site at www.preemievoicesbook.com.

Also on the home page of her web-site there is a 25 minute video, which has several of the book contributors (and a couple of mothers) telling some of their stories to the camera. I found it quietly moving, and encouraging, adults with and without disabilities talk about their lives, and about how they see their prematurity.

Thanks again Saroj, you really make a difference.

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