On the Radio

Posted on 15 August 2013 by Keith Barrington

I was interviewed for an edition of the NPR Radiolab program a couple of months ago. I have only just had the chance to listen to the program, (called ’23 weeks and 6 days’) and I think the emission was rather well done. I am only on for about 3 minutes total, but that was fine, the show was based around the experiences of a couple of journalists who have written about their time with a very preterm baby in an NICU in Florida.

I was pleased that the presenters talked about the issues without searching for simplistic responses.

 
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Don’t text and drive

Posted on 15 August 2013 by Keith Barrington

That might seem self-evident, but texting while driving has become a major cause of road traffic collisions, and other major incidents, involving pedestrians and others.

AT&T have sponsored a new documentary movie (directed by Werner Herzog), which you can see on youtube, about the problem. It is not easy viewing, but very moving.

I was once in a taxi when the driver started texting, he seemed a bit put out when I told him to stop! But at least he did.

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Long term outcomes, Quality of Life.

Posted on 15 August 2013 by Keith Barrington

I heard a presentation of this excellent study when I was in Melbourne last year, and have been waiting for it to be available in print.

There are now about 30 studies of quality of life in subjects who were formerly very preterm babies, as well as a couple of systematic reviews. Many of those studies have been from regional or national samples, and the results have really challenged how we see the lives of our former patients.

This new study is from a different cohort to those previous studies, a cohort which has been studied before for a number of different measures at 2,5, and 8 years of age. It is a cohort which is more recent than many others, born in 1991-1992.

Roberts G, Burnett AC, Lee KJ, Cheong J, Wood SJ, Anderson PJ, Doyle LW, Victorian Infant Collaborative Study G: Quality of life at age 18 years after extremely preterm birth in the post-surfactant era. The Journal of pediatrics 2013.

As in the other studies there is very little difference between any of the quality of life outcomes of the former extremely preterm or extremely low birth weight babies and the term controls. The only differences were a trivial difference in dexterity score, and a slightly lower score for physical functioning. The EP/ELBW patients were also less likely to be sexually active and less likely to get drunk.

Of major importance also, there was no correlation between quality of life and completed weeks of gestational age. As this figure shows:

QUality of life

There are not many infants at the lowest gestational ages, but no sign of an effect on quality of life.

The systematic reviews that I mentioned earlier also show no correlation between gestational age and quality of life; which I think should make us question guidelines for active treatment which use arguments based on rates of short-term impairment to determine at which gestational ages neonatal intensive care is indicated. Also, most large follow up cohorts have shown no effect of GA on rates of impairment, and a systematic review presented at the last PAS meeting, by Dr Moore and colleagues from Ottawa, was also unable to show an effect of GA on cognitive impairment among extremely preterm newborns, if they are examined late enough (4 to 8 years for their study) to have some prediction for the very long term.

If neuro-cognitive outcomes among survivors is not affected by gestational age, and also quality of life among survivors is not affected by gestational age, and is not significantly different to term babies, then I think that it is really only the survival rates which are relevant to decisions making around birth. Decision-making after birth can take into account other prognostic characteristics, including the number and severity of post-natal complications, factors which may be more relevant to the long term.

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Now you know. EUNOs long term outcomes

Posted on 14 August 2013 by Keith Barrington

The European Nitric Oxide study has just published the 2 year outcomes of their trial. The original trial was one of the studies of routine NO administration to preterm babies. In this RCT 800 infants, <29 weeks gestation, with mild/moderate respiratory distress were given 5 ppm of NO for 7 to 21 days o placebo. There was no effect on the primary outcome of survival without BPD.

This new report describes the 2 year outcomes of 630 of the 685 babies who were alive at 2 years. The Bayley 3 scores were identical between the groups, and all other adverse neurologic outcomes, and adverse health outcomes were also similar.

As we noted in the IPD meta-analysis that we published, this trial was similar to the other ‘early prophylaxis’ trials, but also had significant differences. Partly as infants who had severe disease were excluded, (if they needed more than 50% oxygen) and they could be included if on CPAP at randomization, if they needed at least 30% O2.

I think there is now probably no role for routine iNO in early life as primary prevention of BPD. The results of a follow up trial to the Ballard study should not be too long in coming I think, the trial has stopped enrolling according to the clinical trials.gov website. that study is for infants, 500 to 1250 g, who continue to have significant respiratory support at 5 to 14 days of age and get 20 ppm of iNO for about 24 days.

Use to rescue preterm infants with serious respiratory failure in early life is also not currently supported by the literature, although there may be subgroups (such as those with pulmonary hypertension) who might benefit, and should probably be studied.

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Cervical pessaries? Really?

Posted on 13 August 2013 by Keith Barrington

A new study in the Lancet is a multi-center RCT of the use of a cervical pessary to reduce preterm delivery in twin pregnancies.

I must say this sounded a bit unlikely to me, but it turns out there just might be something to it. First, however, the major finding, which was that overall there was no effect on the primary outcome, a composite of poor perinatal outcomes ‘stillbirth, periventricular leucomalacia of grade 2 or worse, severe respiratory distress syndrome of grade 2 or worse, bronchopulmonary dysplasia, intraventricular haemorrhage of grade 2B or worse, necrotising enterocolitis, proven sepsis, and neonatal death within 6 weeks after the expected term date.’

Women were randomized at between 12 and 20 weeks gestation if they had a multiple pregnancy. The pessaires were then inserted and the pregnancy followed. The only frequent complication was a vaginal discharge. The combined outcome was 13% with the pessary and 14% without.

If I say ‘there might just be something in this approach’: it is based on a subgroup analysis, which should always make you skeptical.

There were also 2 significant changes in study design during the trial. 1. They increased the sample size, because they re-considered the analysis and how they were going to account for the twining (only 2% were triplets). 2. They changed the cutoff for the subgroup analysis based on cervical length, as they had too few mothers with a length below 25 mm (the initial cutoff), so they changed the threshold to the 25% percentile, which turned out to be 38mm. This was apparently done before they looked at the results, just based on the numbers of short cervices.

It was this subgroup analysis that was significantly different. The interaction term for the effect of cervical length on the outcome was p=0.01. This was mostly due to more deaths in the controls with short cervix, (and fewer in the controls with longer cervix, but non-significant). So there were 17 baby deaths in the short-cervix controls and 3 in the pessary group. This seems to be due to a shift in the gestational age at delivery of these pregnancies, with fewer extremely preterm <28 weeks (4% compared to 16%) and fewer very preterm, <32 weeks (14% vs 29%).

This is clearly not conclusive evidence, being based on a subgroup analysis, and relatively small numbers of extremely preterm deliveries in this subgroup (n=12 total pregnancies that ended before 28 weeks). But it does suggest that another trial specifically targeting multiples with a short cervix should be considered.

Currently there really isn’t anything else that works. As I have discussed before on this blog, progesterone doesn’t seem to work in multiple pregnancy with short cervix.

Also there is previous work in singleton pregnancies, randomized to receive a pessary at 18 to 22 weeks if the cervical length was under 25 mm, in which preterm delivery (the primary outcome was delivery before 34 weeks) was much lower with the pessary use (7% vs 28%). This reduction was associated with fewer VLBW babies, and fewer complications of prematurity. This is starting to look a little consistent, and the effect size is substantial enough to warrant further studies.

I was intrigued to see what these things looked like, and the 2012 Lancet article has a photo and a diagram, which I reproduce below. There is also an ultrasound picture if you want to go see that.

This is what it looks like:

pessary

And this is where you put it:

pessary

This positioning is described in the figure legend thusly: The smaller diameter of the pessary is fitted around the cervix and the larger diameter faces the pelvic floor, thus rotating the cervix to the posterior vaginal wall and correcting the cervical angle.

How might this work? Well that really isn’t clear, it would be nice to know a bit more about mechanisms, so that better designs could be developed for the future, but for the moment, it is as the editorial in the lancet put it ‘a glimmer of hope‘.

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Breast-feeding the preterm

Posted on 9 August 2013 by Keith Barrington

In order to catch up a little with the last month’s publications, I will post a few things with grouped studies that seem to me to be related.

Alves E, Rodrigues C, Fraga S, Barros H, Silva S: Parents’ views on factors that help or hinder breast milk supply in neonatal care units: Systematic review. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. In a very small number of studies, parents (almost exclusively mothers) felt that knowledge regarding breast-feeding, and reinforcement of the mother’s motivation, as well as flexibility in NICU routines that impact on breast-feeding were important.

Menon G, Williams TC: Human milk for preterm infants: Why, what, when and how? Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. A quick overview of some of the issues regarding breast milk and the preterm. Overstates I think, the proven benefits (there is almost no good evidence that late onset sepsis is reduced, for example, it may well be true, but the evidence is very weak). I think that is important because the better supported benefits (reduced NEC and improved long-term outcomes) are enough to drive a much more active approach to improving breast-feeding rates, without stretching the evidence. They list some of the unknowns regarding maternal and donor breast milk in the preterm. For maternal breast milk the major concerns I think are 1. How important is CMV transmission, and what is the best way to reduce it; and 2. How to individualize fortification of breast milk to achieve optimal outcomes. For donor breast milk the questions are 1. how to assure nutritional quality control, and 2. how to minimize the adverse effects of pasteurization.

Cooper AR, Barnett D, Gentles E, Cairns L, Simpson JH: Macronutrient content of donor human breast milk. Archives of Disease in Childhood – Fetal and Neonatal Edition 2013. I guess in some ways this was predictable: donor breast milk varies a lot. This study uses a set of analyses of donor breast milk to calculate how that variability would affect the nutritional requirements of preterm infants. The answer is, a lot. Even with fortification nearly half of the breast milk samples fail to give enough protein.

Rochow N, Fusch G, Choi A, Chessell L, Elliott L, McDonald K, Kuiper E, Purcha M, Turner S, Chan E et al: Target fortification of breast milk with fat, protein, and carbohydrates for preterm infants. The Journal of pediatrics 2013 This is an initial study showing that individualized fortification of breast milk is indeed possible in a clinical routine fashion. Without too much fuss, using an automated analyzer, they could adjust the fortification of the breast milk in 23 pilot babies, and then give a more optimal nutrition. They compared some nutritional and growth outcomes with 20 matched, routinely fortified controls, and found some apparent growth improvements. This seems to be the way forward for the future.
Finally, and not in preterms:

Welle-Strand GK, Skurtveit S, Jansson LM, Bakstad B, Bjarkø L, Ravndal E: Breastfeeding reduces the need for withdrawal treatment in opioid-exposed infants. Acta Paediatrica 2013. Is it safe for mothers in a methadone program to breast feed? This study suggests that there may be benefits for the baby that were hypothesized previously, the babies have less withdrawal.

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Back in the Saddle

Posted on 9 August 2013 by Keith Barrington

After a long and extremely enjoyable break, I’m back!

Thought I might restart the blog with a few not neonatology things that I enjoyed recently.

This post by Ed Yong on a study of how the malaria mosquito’s mouth parts find your blood. Includes some fascinating videos of the mosquito in action.

Some of you may have heard of a political party in the UK called UKIP. Well one of their members (a member of the European parliament, no less, who wants the UK out of Europe) recently referred to recipients of UK overseas aid as being the inhabitants of Bongo-Bongo land who use the munificence of British aid to buy certain luxuries for themselves. Well there is a great putdown by Afua Hirsch over at the Guardian. ‘A travel guide to Bongo-Bongo land‘

I didn’t know Bears had triplets, but as well as having multiple, non-IVF births, they look after them! The video from a bear cam watching the annual Salmon fishing of the bears shows a mother protecting her cubs from another bear.

In a recent essay in ‘New republic’ Steven Pinker discussed the merits of science, and a scientific worldview. Two of the triumphs of science have been, as he notes, the elimination of smallpox and of Rinderpest. He does not include a more recent and equally dramatic success, the elimination of Guinea Worm. Perhaps because the methods used were so low tech, not fancy vaccines, but filtering drinking water and education. But without science we would never have known the life cycle of the worm, and how to rid the planet of this awful parasite. Which now appears to be gone. Forever.

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Galileo Galilei

Posted on 21 July 2013 by Keith Barrington

As you have may have guessed from the reduced frequency of my posts, I am on vacation! I am actually in Tuscany, in a beautiful villa close to Empoli, which is about 20 kilometers from Florence.

A couple of days ago we went to Florence and among other things visited the Galileo Museum; this is one of the best science oriented museums that I have ever been to. As well as overlooking the Ponte Vecchio, which makes it the best situated science museum that I have visited, it is packed with models of Galilean experiments and inventions, maps and globes dating from our developing understanding of the world, and wonderful explanations of the importance of Galileo, and the developing renaissance knowledge of how the world really is. 

If you are  in Florence and can’t get tickets for the Uffizi, or even if you can, it is worth a visit.

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More SUPPORT controversy

Posted on 16 July 2013 by Keith Barrington

The BMJ has just published an ‘Observations’ piece, with the tag line ‘The Washington Brief’ which would make you think that it is a news item. It is, in contrast, a very biased recounting of some of the controversy raised over the SUPPORT trial consent procedures.  The consent process is described by the author, Sidney Wolfe of Public Citizen, as ‘the lack of informed consent’; a description of the actual procedures that is so prejudicial that I am surprised the BMJ published it. It is noted at the bottom of the article that is was not peer reviewed, so I guess he just got away with saying anything that he wanted.

I have submitted a rapid response which is now on their web site. If there are more published mine will move down the page, but it will remain as the second to last response in the list.

I reproduce the text below:

This ‘Observations’ article by Sidney Wolfe presents a startlingly distorted interpretation of the SUPPORT trial. He starts by making the unwarranted assumption that there was a ‘lack of informed consent’ concerning risks in the SUPPORT trial. He continues to state that this ‘lack of informed consent’ has been staunchly defended’. This is entirely untrue, as Dr Wolfe is already aware.

Prior to enrollment in the SUPPORT trial there was a complete disclosure of the nature of the trial, and the fact that the two saturation ranges being compared were both within the normal standards of care, parents were informed of the masked nature of the intervention, and the fact that the purpose of the trial was to investigate the potential differences in outcomes between the two O2 target ranges. The peer reviewed consent forms were all approved by Ethics review panels set up and operating according to the standards of the OHRP and were signed by parents prior to starting the randomized intervention. How can he possibly characterize this as a ‘lack of informed consent’?

In this article Dr Wolfe notes that the parents were informed that the study was performed to see if there was a difference in outcomes between the two groups, but then claims that parents were not informed that there might be a difference. His claim is nonsensical.

Dr Wolfe is also entirely misinformed about the realities of modern neonatal intensive care. He again makes the claim that normal practice is an ‘individualized standard of care’ that the babies would have received outside of the trial. In reality, normal practice, then as now, is for an NICU to choose a protocolized range of saturations which are used for all very preterm babies in that unit. It is very unusual for an individual preterm baby to need an adjustment of those saturation limits, which prior to CONSENT could range as low as 80% and as high as 100%. More traditional NICUs were still using saturations in the higher range (more ‘conventional’) and many others had already changed to using lower saturations. Dr Wolfe’s misinterprets the term ‘conventional’ as meaning that the lower saturations were somehow outrageously new.

The conclusion that babies in the lower saturation group were therefore being exposed to undisclosed risks is unwarranted. Every analysis of the mortality within the SUPPORT trial, and within neonatal clinical trials in general shows a lower mortality for infants enrolled in trials.

Dr Wolfe mischaracterizes the masking procedure as the use of ‘miscalibrated’ pulse oximeters. Masking is a usual procedure in clinical trials. In this case the masking procedure required the oximeters to read 3% higher or lower (within the target range being investigated) in order to mask the intervention. Dr Wolfe is suggesting that all masked research is unethical because it might have an impact on other interventions required by a patient. If it had been true, in any of the patients, that it was essential to know the true saturation, without the 3% offset, then it was simple to do. Just replacing the study oximeter with another non-study oximeter.

Dr Wolfe ends his distorted article by maligning Dr Modi, suggesting that ‘’The underlying principle behind these arguments opposing fully informed consent in experiments is that it is necessary, via inadequately informed consent, to blur the line between research and standard of care to facilitate more consent and participation.’’ Changing the paradigm from allowing haphazard variations in care to supporting randomized variations in care is not to blur the lines, but to clarify them.

Dr Wolfe seems to suggest that he knows what ‘standard of care’ in the care of the extreme preterm is, and that the hundreds of neonatologists who participated in the design of the trials, writing of the consent forms, and discussion with parents were all malicious ‘experimenters’ more interested in an interesting study than they were in the care of the babies. The reality is exactly the opposite. All babies in these studies WERE treated according to ‘standard of care’, they received identical interventions to other babies in the same NICUs during the same periods. In my own NICU during the COT trial, babies within the study had either saturation goals of 85 to 89, or 91 to 95%. Very preterm babies not in the study had saturation goals of 85 to 94%. Therefore, babies in SUPPORT and the other oxygen trials were not exposed to increased risks. The results of the study have refined our knowledge of the risks of minor variations in oxygen saturation targets; by replacing the haphazard variations in practice with a masked, randomized comparison we have made a great advance in care of the very preterm infant.

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Singing for Cystic Fibrosis

Posted on 16 July 2013 by Keith Barrington

My nephew, Charles Barrington, wrote and performed a song to mark Cystic Fibrosis week 2013. If you appreciate it, send some cash to your local CF charity!

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