End of Life, at Birth

Posted on 19 August 2013 by Keith Barrington

An Op-Ed piece in the NY Times a couple of weeks ago had that title.

I was rather disappointed by the piece, written by an experienced neonatologist; now I suppose for a piece written for the NY Times the fact that it is a very superficial look at perinatal decision-making is somewhat understandable, she makes some good points, but I think it shows a very old-fashioned approach to the issues.

Take this paragraph:

‘Sometimes, I think we doctors need to do more than inform. On occasion, I’ve offered to make a life-or-death decision for parents. If they agree, they are essentially making the decision, but are shifting the burden to me. It’s harder for parents to say, “I unplugged my baby,” than to let the doctor do it.’

I think if the author really thinks that all the doctor should do is inform, then she is very mistaken. Offering to make life-or-death decisions ‘for’ the parents is also extremely disturbing, especially given the whole tone of the article, which makes me wonder how often such a decision would be a ‘life’ rather than a ‘death’ decision. Does she even make that offer if she thinks the decision should be ‘life’?

The whole model of shared decision-making is missing from this piece; rather than imparting knowledge, these difficult discussions need to be about sharing what is important to the parents and the caregivers, exploring values together, working together over the course of the hospitalization to make the best decisions for the baby. There should be no dichotomy between either just informing and then leaving the parents to it, or making the decision in their place.

The whole tone of the article is very negative about the outcomes of the extremely preterm baby, while noting that ‘many’ extremely preterm babies ‘will need treatment long after birth, sometimes for life, at great financial and emotional cost to them and those around them’ she nowhere mentions that the majority do not. And, just as important, that the majority of those who do have long term impairments find their lives quite acceptable.

She also makes the classic, almost universal, error of talking about “survival or having a moderate to severe neurodevelopmental impairment”. I say that is an error as I don’t know how to interpret those numbers; if the risk of that combined outcome is truly 92% (and I imagine she used the NICHD calculator to come up with that exact number) it means something very different if the risk of death is 2%, but that 90% of babies survive with an impairment; compared to the risk of death is 90% but 2 out of 10 survivors have an impairment. We should avoid giving that number, if parents want an estimate of numerical outcomes, talking about the proportion who survive, and separately the proportion who have serious long term impairments among survivors is much more appropriate.

I also think it is an error to focus on the antenatal consultation as the time to make active treatment decisions. Our predictions are so unreliable that making decisions about life-sustaining interventions, at a variable time before birth, when there are great uncertainties about gestational age, and even greater uncertainties abut fetal weight, is really questionable.

What we do need, and don’t really have as yet is a way to predict survival or impairment during the hospital course. We can calculate the percentage survival for the whole group of preterm babies with each additional day of survival, which shows by the way, that once you are born and survive the first day or so, that gestational age has no influence on survival rates. What we can’t yet do is to predict after each day of additional intensive care, or each additional complication, what is the likelihood of going home.

Many of the comments after the piece are also very negatively slanted, many expressing a belief that all these babies end up dependent for life and profoundly impaired.

There are many parent-of-premie blogs out there, some of which I quietly follow. Several have posted responses to Dr Dworetz’s article. See here, and here, and here, and here and here. Those responses are really worth a read, to get parental feelings about the article; they should make you think, I hope, and take some time to reflect on what we mean by Quality of Life, and how that may be different to the Value of a Life.

These parent websites are very often a good source to reflect on how doctors and families interact, for one example the website/blog “life with jack” has a good post “The doctor is not God” which has a list of things that doctors often predict with great certainty, and then turn out to be mistaken, and how that affects families.

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Nutritional Catch-Up

Posted on 19 August 2013 by Keith Barrington

This is my attempt to catch up with some interesting publications from the last few weeks, about nutritional interventions and necrotizing enterocolitis.

Karagol BS, Zenciroglu A, Okumus N, Polin RA: Randomized controlled trial of slow vs rapid enteral feeding advancements on the clinical outcomes of preterm infants with birth weight 750–1250 g. Journal of Parenteral and Enteral Nutrition 2013, 37(2):223-228. 92 babies of 750-1250g birth weight were randomized to a feeding regime which increased by 20 mL/kg/d or 30 mL/kg/d. Although there weren’t any very tiny babies in this study, the results are consistent with all the small number of other prospective studies, that is, there is no effect of how we feed babies on Necrotizing Enterocolitis or other complications. The only effect of feeding babies faster is to get them fed faster! They get off IV feeding more quickly.

Ramani M, Ambalavanan N: Feeding practices and necrotizing enterocolitis. Clinics in Perinatology 2013, 40(1):1-10. That is the opinion also of the authors of this nice review article, they also note ‘Human milk compared with formula reduces the incidence of NEC. Feeding practices do not increase the incidence of NEC in preterm infants. There is no evidence supporting continuous versus intermittent tube feedings in preterm infants… Human milk-based fortifier compared with bovine-based fortifier may reduce the incidence of NEC but additional studies are required.’

That article is part of an issue of Clinics in Perinatology which is all about NEC.

Moore JE: Newer monitoring techniques to determine the risk of necrotizing enterocolitis. Clinics in Perinatology 2013, 40(1):125-134. This one, for example, is about monitoring techniques such as NIRS, a good review which motes that there is little current evidence that we can predict NEC with any of the techniques, but that there is hope for the future.

Stoltz Sjöström E, Öhlund I, Ahlsson F, Engström E, Fellman V, Hellström A, Källén K, Norman M, Olhager E, Serenius F et al: Nutrient intakes independently affect growth in extremely preterm infants: Results from a population-based study. Acta Paediatrica 2013. This population based study tries to answer the question ‘is the poor growth of very sick babies due to their inability to use the nutrition that they are given, or are they just not given enough?’ The answer is that we don’t give them enough, and even after correcting for severity of illness, nutritional intakes were the most important factor in poor growth. Give them more.

Neubauer V, Griesmaier E, Pehböck-Walser N, Pupp-Peglow U, Kiechl-Kohlendorfer U: Poor postnatal head growth in very preterm infants is associated with impaired neurodevelopment outcome. Acta Paediatrica 2013, 102(9):883-888. This is one of the consequences of poor nutrition. Smaller heads. Which are associated with poorer development.

Valentine CJ, Morrow G, Pennell M, Morrow AL, Hodge A, Haban-Bartz A, Collins K, Rogers LK: Randomized controlled trial of docosahexaenoic acid supplementation in midwestern U.S. Human milk donors. Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine 2013, 8(1):86-91. This RCT shows that there is little DHA in breast milk of donors to a milk bank in Ohio, but supplementing the mothers increases their milk DHA content, and increases the DHA received by the baby to within an acceptable range (whatever that is) and certainly suggests that it might be a valuable thing to do, if we can prove that clinical outcomes are improved, which is certainly a possibility.

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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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