Erythropoietin for brain protection in the very preterm? Not worth Penuts.

That isn’t a mis-spelling, just a bad attempt to play with the acronym for a good trial; the PENUT trial, just published in the (FP)NEJM. (Juul SE, et al. A Randomized Trial of Erythropoietin for Neuroprotection in Preterm Infants. N Engl J Med. 2020;382(3):233-43). This was a multicenter trial in infants of at least 24 weeks gestation and less than 28, who either received erythropoietin or placebo and were followed to 2 years of age, with a primary outcome of death or major neurological impairment or developmental delay (NIDD). Hence Preterm Erythopoietin NeUroprotection Trial.

The simplest way to state the results is that they showed no effect; mortality was 13% with erythropoietin and 11% with placebo, and NIDD, among survivors who were evaluated, was 11% with Epo and 14% with placebo.

In more detail the intervention was 1000 U/kg iv every 48 h six times; then subcutaneous at 400 U/kg three times a week until 32 weeks 6 days, started within the first 24 hours of life. Controls received placebo injections, iv and then sham injections during the s/c phase, administered behind a blind by a research nurse. between 22 and 26 months of corrected age the babies had a neuro exam, Bayley-3 and MCHAT (autism screening tool).

Here it gets a bit confusing, there were 941 infants enrolled, randomized 1:1. The primary outcome is only available for 741, in what is called in the abstract a “per-protocol” efficacy analysis. Usually, that term is used when you do a secondary analysis, after the initial Intention-To-Treat analysis, and can be quite different from the ITT if there are a lot of protocol violations (which may be for good reasons). If substantial numbers of controls received erythropoietin, or active treatment babies didn’t get the assigned intervention, then an exploratory per-protocol analysis might demonstrate that the lack of difference between groups (as a hypothetical example) was potentially because of protocol violations, and that maybe the physiological impact would be positive if there had been fewer violations. I don’t think that is what they mean here, I think that they performed an ITT analysis (by which I mean that all babies were analysed according to their assigned group), but one which only includes those who had the neurodev evaluation at the right time.

As you can see in the CONSORT flowchart shown below:

21% of the surviving infants were “excluded”, that is the sum of losses to follow-up, a little over 10% in each group, and incomplete exams (3%), and those outside the 22 to 26 month window (about 6%).

The follow-up rate is certainly less than one would like, especially as non-followed babies are not necessarily the same as babies who are followed. (In some cohorts they tend to have worse outcomes, in others they tend to have better outcomes, it seems to depend on the structure of the health care system).

As you can see from this summary slide of the primary and secondary outcomes any differences between groups were fairly small, and it is possible that a higher follow up rate might have shown a difference in severe cerebral palsy, for example, but it is highly unlikely that the primary outcome (death or severe NIDD) would have been different.

As you can see from this slide the primary outcomes were for severe NIDD, including CP with a GMFCS more than 2, or low results on Bayley-3 cognitive or motor scores below 70. They are described in the text of the paper as being more than 2SD below the mean, but we well know that 70 is not 2 SD below the mean but more like 2.7 SD below the mean of a contemporary group of healthy full-term children.

It is interesting that the rate of Bayley-3 < 70 is lower than most reports for infants of this gestational age, 7.5% low cognitive scores if we put the groups together. The authors explain this by the exclusion criteria having left out the highest risk infants, but I am not sure: as you can see from the flow-chart, only 80 were excluded for “not expected to survive” which is certainly a higher risk group for death or severe NIDD, but the small numbers of other exclusions don’t explain the unusually good Bayley-3 scores. Maybe there is a socio-economic bias among the centres enrolling for this trial, or some other reason, or maybe the 20% not followed would have had worse Bayley scores, or maybe the centres just have good 2 year Bayley outcomes in general, which would be interesting.

In any case, the results are disappointing with regard to Epo, many people were hopeful that Epo therapy would be a partial help in overcoming the disadvantages of being born extremely preterm, the prior smaller studies and systematic review suggested a likely benefit. If you wonder about the dose used in PENUT, then other data provided show that there was at least an erythropoietic effect, active treatment babies were less likely to be transfused and received a lower total volume of transfusion.

The previous systematic review was heavily dependent on the results of Song et al (Song J, et al. Recombinant human erythropoietin improves neurological outcomes in very preterm infants. Ann Neurol. 2016;80(1):24-34). A study from Zhengzhou in China which I missed at the time, probably because it was published in Annals of Neurology, which included 668 babies under 32 weeks, most of whom were over 30 weeks gestation, and most of whom were boys (70%). They had very high rates of PVL (20% among placebo babies), RoP (26%), NEC (14%), Severe IVH (16%), and Sepsis (26%) despite the maturity of the subjects, and the dose was different from PENUT; 500 units/kg every 48 hours x 7 doses. The trial was registered in 2014 after it was performed.

I mention all those details as I think it is clear that the results of the Song et al trial cannot be extrapolated to other jurisdictions with very much lower rates of complications in infants of 30 to 32 weeks gestation. There are also reports of different rates of positive results in trials published coming from different countries, (Vickers A, et al. Do certain countries produce only positive results? A systematic review of controlled trials. Control Clin Trials. 1998;19(2):159-66). That review showed that 100% of published acupuncture trials from China were positive, and 99% of all published trials, of other interventions than acupuncture, from China had positive results. Publication bias may be part of the reason behind this, which is one of the reasons for demanding that all randomized trials be registered before they are started. If they are registered at the same time as analyzing the results or submitting the article there is little point to the exercise, as we will never have any idea which trials were performed, were negative or null, and were never submitted for publication or published.

That review of publication source and potential bias among results is now over 20 years old, has the situation changed? I think those performing systematic reviews need to know. If over 90% of RCTs from a particular source are positive, then within the review a sensitivity analysis excluding studies from that source would be an important part of ensuring the reliability of the results.

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Gene therapy for SMA; who will win the lottery?

There are few things more disgusting than the obscene actions of drug companies that profit off the distress of dying babies and their families.

You might think that the price of a drug would be based on development and production costs and a reasonable profit margin.

You would be wrong.

Drug costs are based on how much the drug company think they can gouge out of our medical systems.

The dramatic, almost miraculous, impacts of gene therapy for Spinal Muscular Atrophy (SMA) made me hopeful that we could perhaps have a long term cure for this most atrocious of diseases. The reality is that the company that is profiting from the years of publicly funded research into SMA is only interested in their profits, and have no interest in the pain of families with a new diagnosis.

For those who are not specialists, SMA is a disease of the nerves which control movements, there are several types with the most severe forms appearing within the first few weeks of life and progressing to respiratory failure and death within a few months, milder forms can allow longer survival, and some more mildly affected people can live much longer lives. It is a recessive condition, so affected babies receive one abnormal gene from each parent, genes which control the production of a protein called SMN. SMN has multiple functions including in spinal motor neurones. If we could correct the genes at an early stage before there are secondary effects, then we could perhaps improve production of SMN, and correct the disease.

Let’s be clear, it is publicly funded research that determined which genes were implicated in this disease, in how the gene controllers were important, what were the precise abnomalities in gene transcription that lead to the reduction in SMN production, what are the relative importance of the SMN1 and the SMN2 genes etc.: the vector used for this disease was developed using public money, and the first trials of gene therapy with the vector in animal models were funded by the NIH as well a studies in transgenic mice which showed correction of the genetic defect and improvement in motor function followed vector injection. The actual product tested and administered to babies in the study that I talk about below was made in the Nationwide Children’s Hospital in Columbus OH, not in the labs of the company sponsoring the study. Interestingly, at least one of the authors on those animal studies was listed as being at the research institute of Nationwide, but the same author is now listed as being an employee of Avexis.

By engineering adenoviruses to carry a normal gene, it was shown in animal models that the motor neurone cells involved in the disease could be manipulated to produce more of the SMN, which might improve function, and finally initial trials in a small number of human babies seemed to be succesful.

Babies with a recent diagnosis were treated with a single intravenous infusion of the vector associated with an engineered human SMN gene and a gene promoter region. A recent publication following up the participants (Lowes LP, et al. Impact of Age and Motor Function in a Phase 1/2A Study of Infants With SMA Type 1 Receiving Single-Dose Gene Replacement Therapy. Pediatr Neurol. 2019;98:39-45) appears to show that those who were treated earlier had better motor outcomes, and those treated with less severe motor abnormalities at the time of treatment had nearly normal scores as they were followed up. The baby treated latest is the one who didn’t really improve on this figure showing the motor function of the participants, with higher CHOP-INTEND scores being better and 64 being the maximum possible score.

https://ars.els-cdn.com/content/image/1-s2.0-S0887899419302802-gr1.jpg

Of note the initial and the follow up studies were sponsored by the manufacturer, and many authors are employees of the manufacturer. In the follow-up paper they only report the outcomes of the 12 babies who received the higher dose, the 3 initial babies who received the low dose seem to have disappeared from the publications, including another publication about the general health outcomes of those 12 babies. (Al-Zaidy S, et al. Health outcomes in spinal muscular atrophy type 1 following AVXS-101 gene replacement therapy. Pediatr Pulmonol. 2019;54(2):179-85). That publication shows that the 12 higher dose babies were in dramatically better health than ever seen in babies with Werdnig Hoffman disease (as we used to call it), and some seemed to continue to improve, by about 2 to 3 years of age. They weren’t completely asymptomatic, many had episodes of needing BiPAP during hospitalisation for respiratory infections, for example.

It is possible that, in the more long term, the therapy will have a limited duration of action, maybe the genes inserted by the vector will be selected out over time, or who knows what else might happen. The longest follow up of the babies is still relatively short. Despite this the therapy has received regulatory approval and is now for sale in the USA.

Of course the producers of the therapy are pricing it to recoup their development and production costs but also to try and make it available for as many babies as possible… NOT!

Avexis the producer (which is part of the Novartis group) has the following nauseating statement on their web page :

Since 2013, AveXis has had one focus: bringing change to those devastated by genetic diseases.

The AveXis culture embraces this mission. As a compassionate and dedicated team, we are enthusiastic about the science behind our work, breaking barriers, and finding answers to difficult questions. We are dedicated to communities affected by rare diseases, and these patients and families are the motivation for everything we do

At least, it is nauseating when you compare those high-flown sentiments to the reality of their actions. The price set for what they are calling Zolgensma is 2.125 million dollars US, for what is intended to be a single, one-time-only dose.

And, in a twist that sounds like it comes from a dystopian Sci-fi novel, the company is holding a lottery to give away 100 doses of the drug to those who win the lottery who cannot otherwise access it, apparently only in countries where the drug is not licensed, which might actually be illegal in many places, and with no follow up of the lottery winners. Canadian parents are already trying to get in on the lottery, as Zolgensma is not currently licensed here.

What genius in the marketing department thought that a life or death lottery was a good idea? Had they just read ‘Hunger Games’, and thought, “wow that sounds like such a great way to do things, how can we use those brilliant ideas with our new treatment”?

Interstingly also, a web page which reports news from the pharmaceutical industry notes that the drug has saved many lives and the industry is ecstatic about their contribution to the health of humanity….. er, no. It notes that the drug made the company 160 million dollars in the first full quarter of availability; there is no mention of the human impact of the therapy, just that it is a good little money maker.

If there is enough profit margin in this drug to give away 100 doses (which clearly doesn’t mean giving away 213 million dollars, but probably willl mean a 213 million dollar tax write-off for the company) then why not reduce the price?

The incidence of severe neonatal SMA, so-called “SMA type 1” is about 1:10,000. With about 90,000 births in Quebec every year we should need to treat 9 babies a year, that would be about 25 million Canadian Dollars a year, for a population of 8 million. For the whole of Canada we are talking about 125 million dollars, and for the whole of the USA that would be about 1.2 billion dollars a year going into the pockets of Novartis.

There is no way our health care systems can bear this sort of profit-taking from industry. In addition to the already incredibly high costs of immune based therapies for malignancies, and other enormously expensive treatments, what will happen when gene therapy for cystic fibrosis becomes available. which is 10 times more frequent?

How can an intervention like this, developed entirely with public funds, be hijacked at the last minute by one of the world’s richest companies?

The only private funding in the development process, it seems, was for the uncontrolled study in 15 babies, which would be very surprising if it had cost more than a few hundred thousand dollars. They will have needed to invest to ramp up a production facility and have good quality control, and so on, but $2,125,000 a dose?

We need to rethink all this. The capitalist model of unrestricted profit-taking with pharmaceutical companies making whatever money they think they can get away with on the backs of dying babies (or adults, or the chronically ill), really needs to be changed.

I don’t know how the scientists involved in the development of this therapy, now working for Avexis, can sleep at night; I guess they now probably own their own yachts so the gentle rocking from the waves helps them to forget that they once had a conscience.

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Oropharyngeal airways for resuscitation of the preterm? Throw them away!

When I saw the title of this new study I thought immediately this has to either be by Peter Davis or one or more of his disciples… former trainees, I mean. In fact it is both:

Kamlin COF, et al. A randomized trial of oropharyngeal airways to assist stabilization of preterm infants in the delivery room. Resuscitation. 2019;144:106-14.

A two center trial from Melbourne and from Edmonton randomized 137 babies of under 34 weeks gestation who needed face mask ventilation in the delivery room. The idea was to determine if routine use of an oropharyngeal airway (OPA) would improve ventilation and therefore improve the efficacy of resuscitation, the primary outcome variable was therefore the presence of obstructed breaths, as seen on a respiratory function monitor during assisted ventilation via face mask in the delivery room.

The main finding is that airway obstruction was much more frequent with the use of the OPA, partial obstruction of at least one attempted inflation occurred 70% of the time with the OPA and 54% without. Complete obstruction was a little bit more frequent without the OPA, but overall proportion of babies havaing any kind of airway obstruction episodes was 80% with the OPA and 64% without.

This points out how frequent airway obstruction is during resuscitation of the preterm infant, even teams with an acute interest in the mechanics of resuscitation find a very high frequency of airway obstruction. The respiratory function monitor looks more and more like a good option for these babies, it is sometimes difficult to know how well you are ventilating a baby, with our current approach trying to avoid overlarge tidal volumes and too much chest movement.

A supplementary finding is that it is often difficult to insert the airway

An attempt was made to insert the OPA in all 67 infants randomized to the intervention, with difficulty experienced in 15 (22%); these were exclusively related to airway opening and inserting the OPA above and behind the tongue. The OPA had to be either down or upsized in these 15 infants. No trauma (bleeding from oropharynx) was seen. Gagging was observed in 6 (9%). During PPV, the OPA was dislodged (pushed out by the movements of the tongue) in 23 (34%) infants. Operators were either unable to insert the airway and maintain the airway in position to provide PPV or felt more comfortable to remove
the airway in order to continue PPV in 19 (28%) infants.

I don’t really think you should throw away the OPA, but they should clearly be kept in reserve for rare cases. Remember the “A” in “Mr SOPA” does not mean an OPA, it means either intubation or LMA.

 

(I made an error in the title of the previous version of this post, which was oropharyngeal masks for resuscitation… oops!)

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Oxygen for resuscitation of the very preterm

One of the paradoxes of neonatal respiratory control physiology is that hypoxia depresses respiration whilst hyperoxia stimulates breathing efforts. In fact it’s not such a paradox, prolonged hypoxia in adults decreases respiratory drive also.

But could this be relevant in the delivery room?

We still don’t know how we should start resuscitation for very preterm babies, it seems likely that 21% oxygen is too low, but how high should we go? If we start with too low an oxygen concentration the infant will stay with a lower oxygen for longer and this may depress their own respiratory efforts, but if we start too high then they may suffer oxidative stress, and we might trigger a cascade of injury to the lungs and other organs.

We really need I guess, multiple trials of differing initial concentrations of oxygen, and differing ways of adjusting the concentration during the first few minutes. The eventual primary outcome of such trials will have to be clinically important complications of prematurity, but as an interim the immediate impact of the intervention is an important pointer to what we should be studying.

Here is one such trial: Dekker J, et al. The Effect of Initial High vs. Low FiO2 on Breathing Effort in Preterm Infants at Birth: A Randomized Controlled Trial. Frontiers in Pediatrics. 2019;7.

In this trial from Leiden and Melbourne they randomized and obtained respiratory recordings from 44 infants born before 30 weeks. Babies were started on either 30% oxygen of 100% oxygen, in the 30% group they followed a current typical practice of increasing FiO2 if the babies SpO2 stayed below the Dawson 25th percentiles; the 100% group were weaned from O2 once their saturations were over 90%. You can see what happened to the SpO2 and the FiO2 in this figure:

https://www.frontiersin.org/files/Articles/494441/fped-07-00504-HTML/image_m/fped-07-00504-g002.jpg

You can see that the heart rates were equivalent in the 2 groups, and that the 100% O2 group rapidly decreased their O2 requirements, so that between 5 and 8 minutes of age they were actually receiving a lower FiO2 than the 30% babies who were increased by protocol to 50% and then 100% if they were below the goals saturations.

The main outcome of interest in the study was the spontaneous minute volume of the babies, which you can see below, the differences were due both to differences in tidal volume and in respiratory rate.

https://www.frontiersin.org/files/Articles/494441/fped-07-00504-HTML/image_m/fped-07-00504-g003.jpg

They also measured other parameters of respiratory effort such as mean inspiratory flow rate, and how much time they needed to have positive pressure ventilation, and showed that the 100% oxygen babies had higher drive.

Because of the rapid wean of FiO2 in the 100% group and the increase in the others there was a lot of overlap of total oxygen exposure and although it was somewhat higher in the 100% oxygen group, there wasn’t really much difference; they also measured one index of oxidative injury, 8-iso-prostaglandin F2α, which wasn’t different between groups.

This study obviously isn’t a good reason to change practice, but it is a good reason to rethink our approaches, and consider impacts of oxygenation on respiratory drive.

I must say I have become allergic to 100% oxygen over the years, and I wonder if 80 or 90% might not be even better? Taking an immature lung bathed in low PO2 fetal lung fluid and exposing it immediately to pure oxygen just doesn’t sound like a good idea. At least mixing a bit of nitrogen with the O2 might help to prevent atelectasis and the rapid influx of polymorphs into the lung while still having the benefits of the increased saturations allowing the rapid development of good respiratory drive.

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Therapeutic Hypothermia post cardiac arrest

This is a bit off-topic for this blog, but many of you will know that cooling is now used for many other patients than just our full-term asphyxias. Adults who remain with depressed levels of consciousness after resuscitation from a cardiac arrest are cooled for 24 hours, data showing better survival are relatively convincing especially after ventricular fibrillation and other shockable rhythms. The effects on adults with asystole or pulseless electrical activity have been less convincing, hence a nice multicenter trial from France in exactly such patients.

Lascarrou JB, et al. Targeted Temperature Management for Cardiac Arrest with Nonshockable Rhythm. N Engl J Med. 2019.

Basically, it worked! The figure below shows the benefit, with the 5 outcomes being death in grey, persistent vegetative state is outcome cerebral performance category 4; 3 is severe disability, meaning conscious but dependent on others for activities of daily life (dark blue); 2 is moderate disability meaning relative independence but includes dysphasia, hemiparesis, ataxia, personality and intellectual changes; 1 is a good recovery with only minor impacts on functtion.

Being alive with a grade 1 or 2 outcome at 90 days was the primary outcome variable which improved from 5.7% to 10.2%, normothermia compared to cooling. There being no difference in mortality, 90 day outcomes were the difference.

What I find striking is the contrast in the interpretation of these outcomes to the outcomes of extremely preterm infants. In preterm infants this would, in many places, be considered going from profoundly bad, and not worthy of intensive care, to a little less profoundly bad and still not worthy of intensive care!

It is interesting that this study was done in France, where, in the same academic centers where these adult patients are being treated, intervention for infants born at 23 weeks is rare. Infants born at 23 weeks who receive intensive care have much better outcomes than these adults.

Makes you think…. I hope.

 

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International variations in outcomes of extreme preterm infants

A publication from an international collaboration of neonatal databases has just appeared, (Lui K, et al. Trends in Outcomes for Neonates Born Very Preterm and Very Low Birth Weight in 11 High-Income Countries. J Pediatr. 2019). It makes very interesting reading, there are significant variations in several outcomes at different gestational ages, with progressive improvements in survival for babies from 24 to 31 weeks in the majority of participating database participants. Below is the annual crude mortality for the whole gestaional age group together (the abbreviations are for ANZN, Australian and New Zealand Neonatal Network; CNN, Canadian Neonatal Network; FINMBR, Finnish Medical Birth Register; INN, Israel Neonatal Network; NRNJ, Neonatal Research Network Japan; SEN1500, Spanish Neonatal Network; SNQ, Swedish Neonatal Quality Register; SwissNeoNet, Swiss Neonatal Network; Tuscan NN, Tuscany Neonatal Network; UKNC, United Kingdom Neonatal Collaborative).

Although smaller samples seem to imply that mortality has plateaued, larger databases (and the size of these databases varies hugely from a total of 1500 babies in one, to over 30,000 in the Japanese) do still show a progressive decrease in mortality as we continue to improve our care of very preterm babies.

The data don’t include babies under 24 weeks because of different approaches in the different countries; distribution of gestational ages also differs somewhat between countries, with the Japanese network reporting 8.5% of the babies were 24 weeks, compared to as low as 5.4% in the Swiss units. That difference in distribution should be taken into account in any comparison.

Also encouraging is that the improved survival has not been accompanied by worse complications, frequency of severe brain injury and treatments for RoP are relatively static despite more survival. There seems overall to be a small reduction in servious brain injury (which includes grade 3 and 4 hemorrhage and persistent peri-ventricular echodensity or echolucency) rates differ between countries (which has many potential explanations, including differences in screening interpretation and definition), but most of the larger database show a reduction between the first and second halves of this period. There is a slightly clearer reduction in RoP receiving treatment also.

In contrast there has been a significant increase in BPD during the interval, except for in Canada, where the rate has been falling. So when the different outcomes are put together as composites, (mortality or treated RoP or severe neurologial injury, with or without BPD) you see this:

Just about everywhere has seen an improevement in survival without SNI or RoP

Much of the data would suggest that the cost of having more babies survive is more lung injury, and in a sense I think that has to be true. More babies who ‘should’ still be in utero with their lungs exposed to the low PO2 lung liquid being secreted into their lungs to help them grow and develop, who are exposed to gases instead containing huge amounts of reactive oxygen, disturbed mucus movement, plasticisers and nasty microbes; that has to mean more lung injury. But the Canadian experience suggests we can perhaps have an impact on the severity of those changes. Of course the definition of BPD used was oxygen at 36 weeks gestation which has limited clinical utility, but for these kinds of large database studies is at least simple.

I think the co-ordinated national quality improvement initiatives are having an impact on outcomes, and whatever it is we are doing is improving the outlook for our patients.

One thing that the publication makes clear is that my comments in a previous post about RoP screening can’t necessarily be directly instituted in other countries. Retinopathy requiring therapy was less frequent in the Canadian Neonatal Network, (CNN) than some other countries, but more frequent than in others. The differences between, for example, Japan and Switzerland are enormous about a 6-fold difference, and the same screening criteria wouldn’t work for the 2 countries.

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Platelet transfusion threshholds: 25,000 even for the highest risk infants?

The Planet-2 trial that I posted about when it first came out showed no benefit among preterm infants, <34 weeks gestation when they received platelet transfusions at a threshold of 50,00 compared to waiting until they dropped to 25,000.

I didn’t find the lack of benefit overall in the high threshold group particularly surprising. What was unexpected was that using the lower threshold actually had benefits in terms of a substantial increase in survival without subsequent serious bleeding, 19% vs 26%. The benefits seemed to be both in death, about a 5% absolute reduction, and serious bleeding, about a 3% absolute reduction. The lower threshold babies also had less BPD, a 9% absolute reduction among survivors.

A newly published secondary analysis of the trial asks the question whether the benefit of a lower transfusion threshold applies to all the risk subgroups, or just to lower risk patients. In other words if a baby is at very high risk of bleeding, then perhaps we should continue to consider a higher threshold. (Fustolo-Gunnink SF, et al. Preterm neonates benefit from low prophylactic platelet transfusion threshold despite varying risk of bleeding or death. Blood. 2019).

To answer this question you could look at specific high risk groups (such as babies who are thombocytopenic in the first 3 days of life); that was already published as a supplememtary analysis with the original paper, and in fact the relative, and absolute, benefit of a lower threshold on the primary outcome was greatest among babies randomized before 72 hours of life, 11% vs 25%.

An alternative method is to determine risk categories from data collected during this trial, which is what this group have done, creating a logistic regression model of risk of the primary outcome (survival without further serious bleeding) and then dividing the infants into quartiles of risk based on the model. They then showed that all quartiles of risk had a benefit from a lower transfusion threshold, and in fact the highest absolute benefit was in the quartile with the highest risk.

This is further evidence that we can apply the lower threshold to all of our preterm babies with throbocytopenia.

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