“The war to end all wars” 100 years on

Among the many moving ceremonies to mark the centenary of the Armistice, a series of portraits of casualties of the first world war were stencilled in the sand around Britain, the project is called “Pages of the Sea”, which is a quotation from a poem from the Caribbean poet Derek Walcott, and now incorporated in a new commemorative poem by Carol Ann Duffy. You can read it on the website for the project, which is here, and see many photographs.

This is a portrait of Wilfrid Owen.

A sand portrait of the poet Wilfred Owen on Folkestone beach

Wilfrid Owen left from Folkestone, the beach where this portrait is found, twice, to go to the front.

He was killed after his second departure, on the 4th of November 1918 just a few days before the declaration of the end of the war, his mother could hear the bells ringing in celebration of the Armistice when she received the telegram one week later informing her that her son was dead. In high school in England we were set a Wilfrid Owen poem to study, much of which I still remember:

Dulce et Decorum Est

Bent double, like old beggars under sacks,
Knock-kneed, coughing like hags, we cursed through sludge,
Till on the haunting flares we turned our backs,
And towards our distant rest began to trudge.
Men marched asleep. Many had lost their boots,
But limped on, blood-shod. All went lame; all blind;
Drunk with fatigue; deaf even to the hoots
Of gas-shells dropping softly behind.
Gas! GAS! Quick, boys!—An ecstasy of fumbling
Fitting the clumsy helmets just in time,
But someone still was yelling out and stumbling
And flound’ring like a man in fire or lime.—
Dim through the misty panes and thick green light,
As under a green sea, I saw him drowning.
In all my dreams before my helpless sight,
He plunges at me, guttering, choking, drowning.
If in some smothering dreams, you too could pace
Behind the wagon that we flung him in,
And watch the white eyes writhing in his face,
His hanging face, like a devil’s sick of sin;
If you could hear, at every jolt, the blood
Come gargling from the froth-corrupted lungs,
Obscene as cancer, bitter as the cud
Of vile, incurable sores on innocent tongues,—
My friend, you would not tell with such high zest
To children ardent for some desperate glory,
The old Lie: Dulce et decorum est
Pro patria mori.
* This is a quotation from Horace “it is sweet and decorous to die for one’s country”


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Under Pressure…

This post “under pressure” isn’t about the classic collaboration between David Bowie and Queen at Live Aid, rather it is about how to wean CPAP. Should we trial preterm babies off for a period every day, or either progressively reduce the distending pressure or just stop it? If we do any of those things, the details of how to do it might make a difference. Is weaning to high-flow cannulae better than just stopping the CPAP and using low flow, if O2 is still required?

A few recent studies are relevant to these questions. The best outcome for such studies would probably be something like clinical pulmonary disease at 2 years of age, and, as an important secondary, some metric of respiratory support use, such as in hospital costs, or total duration of CPAP use. It is unlikely we will ever have adequately powered studies to show that stopping CPAP by weaning pressures, compared to progressively weaning off-CPAP time (as an example of a study that could be done) will change the number of infants who are re-admitted for respiratory decompensation during the first year of life.

I guess you could do a study with enough power to show whether one way of weaning, compared to another, led to fewer infants being on oxygen at 36 weeks (i.e. classical “BPD”) but I am increasingly sceptical about this as a measure of pulmonary injury. Acutely reducing lung inflammation with steroids (for example) might decrease the numbers of babies with “BPD” without actually improving the long-term pulmonary health of any of them. Similarly maintaining good lung volume might do a similar thing, whereas overdistension might do the opposite, but the consequences for long term pulmonary health might still be unclear. Despite the limitations of this definition, however, it is still usually collected as the primary variable reflecting lung injury in the preterm.

The Cochrane review of CPAP weaning methods hasn’t been updated since 2011, so the studies below are not included in that review.

Here is a selection of recent publications, starting with the most recent:

Jensen CF, et al. Sudden vs Pressure Wean From Nasal Continuous Positive Airway Pressure in Infants Born Before 32 Weeks of Gestation: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(9):824-31. This Danish group enrolled 372 babies, less than 32 weeks gestation, at least 29 weeks Post-Menstrual Age (PMA), on CPAP for at least 24 hours, <8 cmH2O and <30% O2. They were randomized to either suddenly stopping the CPAP, or decreasing by 1 cmH2O every 24 hours until they reached 4, then stopping. The primary outcome was weight gain, which wasn’t different, and all of the secondary outcomes, including those related to lung function and respiratory support duration, were similar between groups. According to the way the manuscript is written a baby on CPAP of 4 would have been eligible for the study, in which case the intervention in the 2 groups would have been identical. A baby on a CPAP of 5 would have frequently only had 1 day difference in duration of CPAP support, unless the reduction to 4 was not tolerated. The median CPAP at randomization was actually 6 in each group. Overall there were no differences in any outcome when the whole group was analyzed. In a subgroup analysis of babies <28 weeks gestation (n=58), more babies were weaned at the first attempt with the gradual pressure wean than the sudden wean, but they had just as long on oxygen, just as many on oxygen at 36 weeks etc.

Yang CY, et al. A randomized pilot study comparing the role of PEEP, O2 flow, and high-flow air for weaning of ventilatory support in very low birth weight infants. Pediatr Neonatol. 2018;59(2):198-204. In a study from Taiwan, babies < 1500g and <30 wk GA on CPAP 5 to 7 cmH2O, were randomized when they weighed at least 750g and on no more than 25% O2. There were about 180 babies in 3 groups: 5 days of CPAP 4-6 cmH2O; progressively increasing time on 0.2 L/Min O2; progressively increasing time on 1.5 L/min of air. They showed a shorter duration of CPAP in the 2nd group, but no other relevant differences, and the 2nd group may well have been unnecessarily hyperoxic, and had more RoP and BPD than the other groups.

Eze N, et al. Comparison of sprinting vs non-sprinting to wean nasal continuous positive airway pressure off in very preterm infants. J Perinatol. 2017;38:164. In Los Angeles/ Orange county, 80 babies of 23 to 30 weeks GA, who had reached at least 26 weeks PMA, and were on CPAP for at least 24 hours, at 5 to 6 cmH2O were randomized to progressively increasing times off CPAP versus reducing CPAP to 5 cmH2O for at least 96h, then stopping the CPAP. In either group they could have nasal cannulae up to 2 L/min if needed and up to 30% O2. The primary outcome was succesful weaning on 1st attempt, and there were no differences in any outcome between groups.

Amatya S, et al. Sudden versus gradual pressure wean from Nasal CPAP in preterm infants: a randomized controlled trial. J Perinatol. 2017;37(6):662-7.   A group from New York studied 70 babies on a CPAP 5 and 21% O2, who either had CPAP reduced by 1 cm every 8h down to 3 cmH2O, or just stopped. The primary outcome was the success of the first attempt to wean, which was more frequent in the gradual pressure wean group, but no other outcomes were different including total duration of oxygen therapy, and duration of CPAP, or weight gain.

Nair V, et al. Effect of Nasal Continuous Positive Airway Pressure (NCPAP) Cycling and Continuous NCPAP on Successful Weaning: A Randomized Controlled Trial. Indian J Pediatr. 2015;82(9):787-93. A study from Calgary studied babies of 25 to 28 weeks GA who had been extubated and were on CPAP for at least 72 hours and were down to 4 cmH2O. They were either left on for another 72 hours then taken off, or they were placed on nasal cannulae at 1 L/min for progressively increasing periods. The primary outcome was succesful weaning at the first attempt, and it did not differ between groups. None of the secondary outcomes differed either.

Tang J, et al. Randomised controlled trial of weaning strategies for preterm infants on nasal continuous positive airway pressure. BMC pediatrics. 2015;15(1):147. In Sydney, 60 babies who were on CPAP of 5 or less, were studied in a 2X2 factorial design, HFNC vs no HFNC after wean, and sudden wean versus gradually increasing time off CPAP (starting at 6h on and 1 h off). Primary outcomes were 1) BPD (O2 at 36 wk); 2) days pf respiratory support; 3) days of hospital stay; and 4) days to achieve full suck feeds. None of the primary outcomes differed between comparisons, (high flow vs no high flow, or abrupt wean compared to progressively prolonging time off. But the abrupt wean group  had fewer days CPAP (10.5 vs 16.5 d; p = 0.02), lower PMA when CPAP was stopped (33.1 vs 34.6 wks; p = 0.05), and fewer days pressure support (21.5 vs 27.5 d; p = 0.04).

Rastogi S, et al. Gradual Versus Sudden Weaning From Nasal CPAP in Preterm Infants: A Pilot Randomized Controlled Trial. Respiratory Care. 2013;58(3):511-6. This study, from the same group in New York, studied a progressive increase in time off compared to sudden stopping of the CPAP in 56 babies of 32 weeks GA or less who had been on CPAP at least 48 hours. The primary outcome was success of the first weaning attempt, which was not different between groups, none of the secondary outcomes was significant either.

Todd DA, et al. Methods of weaning preterm babies <30 weeks gestation off CPAP: a multicentre randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2012;97(4):F236-40. This is the CICADA trial, in which 177 babies on 4 to 6 CPAP and <25% O2 were randomized to one of 3 methods, sudden wean, progressively increasing time off CPAP, and progressively increasing time off combined with moderate flow nasal cannulae (0.5 litres/min, variable FiO2). Babies in the sudden wean group had shorter time on CPAP, came off CPAP at an earlier post-menstrual age, were less likely to be on oxygen at 36 weeks and went home earlier.

What to make of all that? Well it seems that there is no advantage of weaning by progressively increasing time off in any of the studies, and it may well lead to more failures and a longer duration of O2 therapy. It may be that a progressive weaning of pressure to 3 or 4 cmH2O leads to fewer failures in the short term, but there doesn’t seem to be a big advantage, compared to just stopping from 5 cmH2O when the baby satisfies readiness criteria, which were different among studies, but generally required a low stable FiO2 and little respiratory distress, without significant tachypnea.

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More about platelets

The recent RCT comparing transfusion thresholds of 25,000 per mm3 to 50,000 in very preterm babies has generated a great deal of discussion. The result was somewhat unexpected, I think. I would not have been surprised to find that there was no impact on hemorrhage, but the increase in mortality surprised me.

Curley A, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. NEJM. 2018. The PlaNet2 MATISSE trial.

We should always be circumspect when evaluating trials that have a composite primary outcome, in this case “death or serious bleeding’. Does it make sense to put the different parts of the outcome together? Are they likely to be of approximately similar frequency, and of approximately similar importance to families? Are they likely to change in the same direction, and if they do not, then how will we interpret the results?

I think this composite outcome has some validity, especially if the definition of serious bleeding is restricted to bleeds that are potentially life-threatening.

When we examine the results there were fewer babies with the primary outcome in the low threshold group, 19%, compared to the high threshold group, 26%. This outcome was made up of death (low threshold 33/330 (10%), versus higher threshold 48/326 (15%) OR, 1.56 (95% CI 0.95–2.55)) and major bleeding episodes (low threshold 35/330 (11%) versus higher threshold 45/328 (14%) Hazard Ratio, 1.32 (95% CI 1.00–1.74))

Remember, however, that that is only mortality up to 28 days after study enrolment, we don’t know if mortality by the time of discharge was different between groups. We do know from the data in table 2 that by 36 weeks, when the outcome of BPD was determined, there were 50 deaths in the low threshold group, and 60 deaths in the high transfusion group, which is probably consistent with a chance effect. It shows also that between 28 days of age, and 36 weeks postmenstrual age (if we assume that the deaths were among babies less than 32 weeks gestation) there were 17 deaths in the low threshold, 25,000, group, and 12 deaths in the higher threshold, 50,000, group.

There are one or two other things about the trial that are a little confusing, only 90% of the babies in the high threshold group actually had a transfusion, whereas to be in the trial the babies had to have a platelet count under 50,000, so surely 100% of them should have had a transfusion, in the article it is noted that the platelet counts increased to above 50,000 while they were waiting for the platelets, but, once I have decided to give platelets we almost always have them in the NICU to be given within an hour, so it is very unusual to have another platelet count between ordering the platelets and giving them, so I find that a little confusing. In the article it is noted that there were 94 platelet transfusions in the high threshold group that should have been given and were not (and 30 in the low threshold group). There is a per-protocol analysis in the online supplementary materials, which shows almost identical differences between the 2 groups when only those babies who actually followed the protocol are included: mortality 10% vs 14%, and major bleed 9% vs 14%.

Another question to ask is whether or not this is biologically plausible. I think it is, platelet transfusions are pro-inflammatory, they have been associated with TRALI (transfusion related lung injury) in adults, and platelets prepared for transfusion release CD40 ligand (whatever that is) which activates cyclo-oxygenase. So there are potential pathways for adverse effects, which could be diverse and could potentially increase lung injury and other complications. In adults platelet transfusions for thrombocytopenia have also been associated with excess thrombotic complications, again a potential risk for our preterm patients.

My final question is the following : what is MATISSE? I understand the acronym PLaNEt2, even though I can’t remember which letters are capitalised, but what on earth is MATISSE doing there?

In the supplementary data we can see that infants who were IUGR did not have any difference in their incidence of the primary outcome (18% vs 20%) between thresholds, but beware, the p-value for the interaction was 0.3, so we shouldn’t make too much about that as a subgroup analysis, also the overall incidence of the primary outcome was not much different from the babies who were not growth restricted. Of course IUGR babies can get sepsis and NEC also, so those babies weren’t necessarily in the trial because of early onset thrombocytopenia associated with IUGR. Those babies with IUGR, maternal hypertension, and/or placental insufficiency are often thrombocytopenic in the first days of life, and have a reduced proportion of immature platelets. Those with consumptive coagulopathy and an increased proportion of immature platelets often have other derangements of coagulation, and I think are probably at higher risk of bleeding. If the authors have the data it would be fascinating to see whether babies with low production of platelets, due to placental insufficiency, have a different incidence of complications, and a different response to platelet transfusions, to those with platelet consumption.

I think we should be careful making excessive claims for a study with a result like this, especially when the 2 parts of a composite outcome are both barely at the threshold of what is classically considered to be statistically “significant”. On the other hand, as I mentioned before, these are the only reliable data we have, and there is no sign at all of a benefit to transfusion at a higher threshold. So for preterm babies who are not actively bleeding, I for one will no longer transfuse unless they fall below 25,000.

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Platelet transfusions don’t prevent bleeding (and may increase mortality).

When do you give a platelet transfusion? You could easily ask 10 different neonatologists and get 15 different answers. I would be one of those who gave several different answers depending on the clinical situation, believing that thrombocytopenia of different aetiologies probably should be transfused at different thresholds, but not knowing the right threshold for any condition. I thought that platelet transfusions were pretty safe, however, so if a colleague transfused at 50,000 a baby that I would have let fall to 30,000, it didn’t bother me very much.

Questionnaire studies have highlighted the differences in transfusion approaches and practices have been analyzed in studies such as this one,  in which 1/3 of transfusions were given to babies with a count over 50,000 (per cubic millimeter, I won’t repeat the units after this). There was never, however an appropriate evidence base to decide on thresholds.

To answer the question I think you should, first of all, study separately the babies with early thrombocytopenia due to alloimmunization, and the few due to maternal auto-immune thrombocytopenia. Maybe you should also eliminate those with thrombocytopenia associated with placental failure/IUGR, and then randomize the remaining babies, many of whom would have sepsis, or NEC, or CMV, to receive platelets at different thresholds, and see if the higher threshold reduces bleeding compared to a lower one. I would probably leave out the IUGR babies as they almost never seem to bleed, but that may not be true, and we certainly need to know.

That is just about exactly what was done in the just-published PLaNeT-2 trial, which just appeared on-line at the formerly prestigious NEJM. Curley A, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. New England Journal of Medicine. 2018.

This trial enrolled babies of less than 34 weeks gestation and included babies with IUGR: (the protocol has previously been published (Curley A, et al. Platelets for Neonatal Transfusion – Study 2: A Randomised Controlled Trial to Compare Two Different Platelet Count Thresholds for Prophylactic Platelet Transfusion to Preterm Neonates. Neonatology. 2014;106(2):102-6) and the whole protocol is available as a supplementary file on the NEJM.org).

Babies with a platelet count of less than 50,000 who had a head ultrasound less than 6 hours previously were randomized. I guess they did this by screening babies with a platelet count of less than 100,000, and performing a head ultrasound if they thought they would become eligible. Babies who had a hemorrhage within the previous 3 days were not eligible.

The primary outcome variable was survival to 28 days (after randomization) without a major hemorrhage : “The outcome of “major bleeding” included intracranial hemorrhage (leading to neurosurgical intervention or radiologic imaging showing midline shift), intraventricular hemorrhage filling 50% or more of the cerebral ventricle, pulmonary hemorrhage (fresh bleeding through an endotracheal tube with increased ventilatory requirements), frank rectal bleeding, and severe bleeding (fatal bleeding, life-threatening bleeding associated with shock, or bleeding requiring fluid boluses or red-cell transfusion). Our definition of rectal bleeding was pragmatic; we defined any amount of fresh visible blood as rectal bleeding”.

660 babies were enrolled in 43 trial sites in the UK, Ireland, and Holland. When transfused babies received 15 mL/kg of platelets. Study size was determined from an expected 20% incidence of major bleeds in the low threshold group, and a desire to detect a reduction to 12% with a higher threshold

The 329 babies in the 25,000 threshold group had 61 major bleeds or deaths prior to 28 days, similar to the hypothesized rate at 19%, and the 324 babies in the high transfusion group had 85 bleeds or deaths which is 26%, for an Odds Ratio of 1.57 (95% confidence intervals 1.06, 2.32).

As you can see from the table with the maine results below, the difference was mostly in survival, although there were a few fewer bleeds in the 25,000 threshold group.

Most of the babies were several days old when enrolled, and many were septic or had NEC. There is really no evidence at all of any benefit of transfusing at a higher threshold from these numbers.

I can’t find in the publication or supplemental data the numbers of babies who survived to discharge, which is much more relevant to me than survival to 28 days after enrolment, if the differences disappear over the subsequent few weeks to discharge (the babies were on average 26 and a half weeks gestation, and about 750 g birth weight so they would have been around for several weeks after the trial) then the implications might be different.

Despite that, I think the lack of any apparent benefit, and possible harm, from transfusing more liberally, and given that this is the only prospective reliable data on outcomes of different platelet transfusion thresholds in the premature, babies at risk of bleeding from thrombocytopenia should be left to fall to 25,000 unless they are actively bleeding. Or maybe even lower.

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Heads up?

A new RCT published in the Journal of Perinatology suggests that a midline head position with head elevated at 30 degrees might reduce severe intracranial hemorrhage. (Kochan M, et al. Elevated midline head positioning of extremely low birth weight infants: effects on cardiopulmonary function and the incidence of periventricular-intraventricular hemorrhage. J Perinatol. 2018). The authors randomized 180 babies of less than 1 kg birth weight to either prone positioning with the head turned every 4 hours, or supine, with the head maintained in the midline, and placed on a wedge-shaped frame inside their incubator with a slope of 30 degrees.

They note in the introduction that maintaining the head in the midline has become part of some quality control guidelines for reduction of IVH. Even though that is true, I am not aware of any prospective trials that show an impact of head position on IVH, and the authors of this study do not quote any. There are several physiologic type studies that have examined the very short term consequences of different head position, but none have demonstrated that those changes are either persistent over 2 to 4 days, or aetiologically associated with intracranial bleeding. The Cochrane review of the issue (from 2017) found 2 studies that compared supine midline positioning to supine lateral head positioning (n=110 total), and found no evidence that there was an impact on the frequency or severity of IVH.

This trial report leaves several unanswered questions, partly because it doesn’t follow CONSORT guidelines. Specifically regarding randomization procedures, the randomization was “using a block randomization table” and was “performed using SAS V9.4” CONSORT guidelines do require the method of generation of the randomization sequence, but also require a description of the mechanisms of allocation concealment, and the implementation of the whole process.

The way it is reported leaves open the possibility that investigators knew which group the next patient would be enrolled in. There are also a few other things that are unclear, the report notes that there were 60 infants who were twins, and that they were randomized individually, but then in the final two groups there were only 29 twins. This seems to imply that infants were randomized, but then did not participate in the study, the major exclusion factor being that an investigator was not available to do the initial ultrasound, which was done immediately after the baby was in the randomized position. That also implies that once a baby was randomized and placed in the position, the ultrasonographers availability would be evaluated. This also leaves a chance for unconscious bias in enrolment.

The primary outcome variable of the study was “the incidence of PIVH”, (that is periventricular and intraventricular hemorrhage) although it is not named as being the primary outcome variable. The purpose of the study is described as being to determine whether the body position would “decrease in the incidence of PIVH” [sic] and the sample size was calculated based on a hypothesized decrease in PIVH from 40% to 20%.

I can’t find a registration record for this trial, which would list the primary outcome variable, and there is no registration mentioned in the manuscript.

Amazingly enough, there is no presentation in the publication of a statistical analysis of the primary outcome variable, in the abstract the primary outcome variable is not mentioned at all.

So here is the analysis of the primary outcome variable: there were 34 infants with PIVH in the head elevated group, and 31 infants with PIVH in the prone group; 38% vs 34%, a difference of 3.3% (95% confidence intervals -11%, +18%). This is clearly a result that could have arisen by chance, in other words this is a negative trial, and secondary outcomes that might be different between groups can only be hypothesis-generating.

Unfortunately the abstract only refers to 2 secondary outcomes, and doesn’t mention the primary. As there is no registration record or published protocol we do not know if those secondary outcomes were chosen after the results were examined or before. Those secondary outcomes are arguably more clinically important than the primary outcome; “grade 4” hemorrhage and survival. Both of those were slightly better in the head elevated group.

The incidence of “grade 3 and grade 4” hemorrhage in the prone/flat babies was 20%, and in the head elevated babies was 12.2%. I put those together to compare to recent data from the Canadian Neonatal Network, for which in babies less than 1kg the incidence of grade 3 and 4 hemorrhages  is around 10%.

Also of interest, all but one of the babies in this study each group of this study were intubated on day 1, and the authors never state if there was a minimum weight for eligible babies.

I think it is a real shame to take the time and effort to do a worthwhile trial like this, and not register it, not make the protocol available (either as supplemental information with the publication or by publishing it), and not report it according to CONSORT guidelines.

I would say that the results do show quite a high incidence of serious hemorrhages in the flat/prone group, and if the random allocation was indeed concealed, the trend to fewer serious hemorrhages in the elevated/supine/midline group is something that warrants further investigation.

Keeping the baby’s head midline, supine and 30 degree elevated positioning means that the infant can’t be prone, and they can’t go in kangaroo, at least not the way it is normally done. So we will need to know if this is a real effect, and if so which part of the positioning is important, elevation, supine positioning, or head midline. Many babies in the category of less than 1000g birthweight are at quite low risk of serious hemorrhage, larger inborn babies who have completed steroids, and especially those who are never intubated, uncommonly develop PVHI. A study in babies selected for higher risk would need fewer numbers, and might be easier to get completed in a reasonable time. The intervention is cheap so keeping organizational costs to a minimum might make a trial with a high potential impact, at relatively low expense.

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Active intervention at 22 weeks gestation, is it futile?

In order to respond to the question posed in the title we need first to agree on what “futile” means. It could mean “it never works” or, “it can work but the ultimate result is so bad that it isn’t worth doing”, or “it works so rarely that the effort and resources required are enormous, and it therefore isn’t worth doing”.

In neonatology, and clinical care in general, the term has been used to mean each of those 3 things (you could probably come up with other definitions), the response to the question depends on which you think is most appropriate.

Clearly “it never works” is not true, sometimes babies born between 22 weeks and 22weeks and 6 days do survive to go home.

In fact the proportion of survivors can be impressively good. (Backes CH, et al. Outcomes following a comprehensive versus a selective approach for infants born at 22 weeks of gestation. Journal of Perinatology. 2018). In this article the authors compared outcomes between a center in Sweden (Uppsala) and one in the USA (Nationwide Children’s, Columbus Ohio). There may be multiple differences between the populations and the medical approach, but the authors focused on what is probably the most important, that is the proportion of mothers and babies with threatened profoundly preterm deliveries who received comprehensive active care.

You could probably characterise the approaches as “Opt-out”, in Uppsala, the default approach is to counsel the parents with the attitude that active intervention is usual and is encouraged by all the team, compared to “Opt-in” where the team attempts to obtain a consensus regarding active intervention, and the parental choice is the priority.

In the article the authors refer to these approaches as a comprehensive approach, and a selective approach.

In Uppsala over a 10 year period (2005-2016) there were 33 mothers who delivered 41 live born infants between 22 weeks and 22 weeks + 6 days best-guess gestational age. All chose active intervention, all received antenatal steroids (and 85% were able to have a 2nd dose), all had surfactant in the delivery room by a team being led by a neonatologist, and 38 survived to NICU admission, none had a cesarean delivery.

In Columbus over the same period there were 64 mothers who delivered 72 babies. Twenty percent (13) received steroids, and 9% (6) had 2 doses. There were 16 babies who had active interventions, 56% (9) had surfactant in the delivery room, a neonatologist was present 75% of the time (11) and 31% (5) were delivered by cesarean (another 2 mothers who did not have active neonatal care also had a cesarean).

Fig. 2

You can see from these survival curves the dramatic difference in mortality between the 2 centers when you include all the live born infants (panel A) or only the babies that received active interventions (panel B).

When the analysis was corrected for multiple risk factors, the relative impact of being born in a center with uniform comprehensive care was actually increased. In other words the babies in Uppsala receiving active care were not heavier, or with lower risk factors, in fact the opposite is true, birth weight averaged 489 vs 527 g and there were more twins. The Odds Ratio of survival after correction was 14.47 (95% CI 3.09, 68.7) in Uppsala compared to Columbus.

This post is by no means a criticism of Columbus, they seem to have an approach similar to many centers in North America, indeed, they are more open to active intervention at 22 weeks than some centers, which refuse to intervene. Their survival rate among actively treated babies is well within the range of those reported for good quality centers. I applaud them for collaborating in this study. Survival to hospital discharge was 53% in Uppsala, and 8% in Columbus, but 19% among those who received active care.

So it is clear that active intervention at 22 weeks cannot be called futile, if by which we mean it never works. But what about the “ultimate result”? This article also includes some follow-up data from all of the survivors at Columbus, and all but one of the survivors in Uppsala. In Columbus all of the survivors had moderate to severe impairment. In Uppsala 20 of the 21 survivors were evaluated, 11 had no impairment, 2 were mildly impaired, and 5 had moderate to severe impairment.

Is the team in Uppsala unique? Are they the only ones to achieve such results, such that we cannot think of extending their success elsewhere? The group in Cologne (Mehler K, et al. Survival Among Infants Born at 22 or 23 Weeks’ Gestation Following Active Prenatal and Postnatal Care. JAMA Pediatr. 2016;170(7):671-7) have published their results of an approach that lies somewhere between these 2 centers, that is a selective approach, but one that ends up with a higher proportion of active intervention. They report 45 live births at 22 weeks, 28 of whom received active interventions (62%), they had 61% survival among those 28 babies at  22 weeks, or 38% if expressed as a percentage of live births.

Are such results possible in North America?

I was just invited as a guest speaker in Iowa, at their first symposium on care of the periviable infant. This was a very high quality small symposium, presentations regarding approaches to the profoundly preterm infant, use of steroids, clinical practices, nursing practices etc. Much of the discussion after the talks was focussed around practices at the University of Iowa, because they have had a policy of encouraging active intervention for many years at 23 and then at 22 weeks. That policy has led to an amazing depth of experience, and a great wealth of knowledge.

Although they are currently trying to publish their results, and therefore there are not a lot of references that I can give, their results of survival among all liveborn babies at 22 weeks gestation, between 2006 and 2016 are 59%. In the most recent period that appears to be more like 65%. They are currently in the process of publishing some results, so I won’t give away any more details, but I am confident that the survival figures are accurate.

Centers who usually, or almost always, give active care to the most immature infants at 22 weeks have survival figures that are better than I thought was possible a few years ago. To achieve such a result you must have a coordinated approach with obstetrics, and administration of steroids whenever active intervention at that gestation is likely to occur. A positive attitude is very important, a belief that it is possible to have good survival, both in terms of percentages and in terms of quality of life of survivors. In Columbus there were a number of families in which there was “inconsistent care”, i.e. the approach of the obstetrical and neonatal teams differed, very often that is active intervention at birth but no steroids being administered, despite having the time to do so, but we don’t know that specifically from this study. The other point is that active intervention does not imply cesarean delivery, mode of delivery is a separate decision, and making that decision requires other considerations, such as the intended reproductive future of the mother. Very good survival without using cesarean delivery is possible.

Is there a downside? If you frequently institute active intervention in babies at such high risk, there will be many complications. As you can see from the data from Uppsala, there were several late deaths, one after 226 days of NICU care, whereas in Columbus death usually occurred early, the latest being at 10 days. The frequency of complications in all of these cohorts, (NEC, sepsis, BPD, RoP brain injury on ultrasound) is high. But survival at quite reasonable frequency is possible, in multiple centers, and many survivors do not have major impairment.

I don’t think that futility can any longer be used as an argument for not actively intervening at 22 weeks.

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Prebiotics and preterms and probiotics.

A selection of recent publications, regarding the issues in the title, that I find interesting and which seem to tell a consistent story.

From Nick Embleton’s group the following interesting study (Stewart CJ, et al. Longitudinal development of the gut microbiome and metabolome in preterm neonates with late onset sepsis and healthy controls. Microbiome. 2017;5(1):75) As an aside, I hate journals that put the methods after the discussion, it makes publications that have no chronologic sense, and the methods are the most important part of an article. I think that peer review would be improved if the only thing the reviewer got to see before deciding whether an article was worth publishing or not, was the methods section. The only way to know if results are reliable, and a discussion is reasonable, is from the methods. It might be OK sometimes if everyone always uses the same methods for an in vitro assay, I guess, but the most important part of a study involving humans, or samples from humans, are the characteristics of those humans, how they were recruited, how samples were obtained etc. etc. (End of small rant).

In this journal the abstract doesn’t even have a section marked “Methods” the only thing we know from the abstract about what was done is the last sentence of the “Background” section : “We performed temporal bacterial (n = 613) and metabolomic (n = 63) profiling on extensively sampled stool from 7 infants with LOS and 28 matched healthy (no LOS or NEC) controls.” In the first publication from this study, the authors described sequential stool samples from 318 preterm infants, of which there were 7 cases of NEC, who were matched to 28 controls, by gestational age, birth weight, and delivery mode. In that publication they showed that there were several patterns of gut colonization (which changed over time) and that the pattern with the microbial highest diversity never preceded NEC. As far as I can tell the babies were all 30 weeks or less gestational age.

In the new publication they report similar methods for 7 of the infants who developed late-onset sepsis (culture-positive), again compared to matched controls without sepsis or NEC.

The gut microbiome of infants with LOS were highly individual and dynamic through time. The pathogen identified by blood culture was one of the most abundant OTUs in the gut microbiota at diagnosis, with the corresponding genus from the gut microbiome the most abundant in four cases and second most abundant OTU in two cases (Fig. 1). An exception was Staphylococcus epidermidis LOS in infant 251, which was the seventh most abundant genus at diagnosis. In all cases, the genera of the bacteria isolated in diagnostic blood culture were present prior to LOS diagnosis.

Here is that figure 1

Fig. 1

Area plots showing the temporal development of the microbiome in infants diagnosed with late onset sepsis (LOS). Dashed red lines represent the day of LOS diagnosis with the bacteria isolated from blood culture identified. Dashed black lines represent the start of an antibiotic treatment.

You can see here the case 181, for example, who had predominant E coli in the intestines prior to having sepsis with the organism, the same for case 172 and Enterococcus.

An OTU is an “operational taxonomic unit” and is a term used to define a group of bacteria that share the same 16s RNA sequences within a certain percentage similarity, (often around 98%) it is not exactly the same as a species or a genus.

They also showed that when you have lots of Bifidobacteria, you were a control, i.e. you didn’t get late-onset sepsis. The metabolomic findings in the gut seem to reflect the bacterial activity, at the time of diagnosis of sepsis, with Galactose metabolism being more active in the controls, and being associated with Bifidobacterial presence.

Jost T, et al. Impact of human milk bacteria and oligosaccharides on neonatal gut microbiota establishment and gut health. Nutr Rev. 2015;73(7):426-37. This is a review article from a Swiss group very active in the area, mostly interested it seems, in normal full term infants and how their gut gets colonized. They point out the importance of maternal-neonatal transfer of organisms such as Bifidobacteria and Lactobacilli. They discuss the presence of prebiotic molecules in milk, specifically those that are probably most important for maintaining the growth of probiotic organisms, the oligosaccharides, known as HMOs, human milk oligosaccharides, it seems to me from my reading that the HMOs which are the most important may well be the fucosylated HMOs, but sialylated HMOs might also be crucial, or the balance of different types.

Even though HMOs are a major component of breast milk, human infants can not digest them. They seem to be present solely to feed probiotic organisms, Bifidobacteria have specific glycosidases which digest HMOs, which most pathogens do not. The situation becomes even more complex in the preterm infant, in whom abnormal gut colonization with pathogens might actually be worse in the presence of some HMOs, which are neither fucosylated nor sialylated, those HMOs seem to be associated with increased growth of Enterobateria (the group that contains many familiar Gram-negative pathogens).

Breast milk from mothers who deliver preterm seems to have a lower and much more variable proportion of the HMOs fucosylated, whereas in term delivering mothers it was very consistent at just over 60%, in another study from the productive group at UC Davis.

Aakko J, et al. Human milk oligosaccharide categories define the microbiota composition in human colostrum. Beneficial microbes. 2017;8(4):563-7. This study showed that the different colostrum samples (from mothers delivering at term by elective caesarean) had differing concentrations of HMOs of differing types, and the types of HMOs were strongly associated with what organisms were most abundant in the microbiome of the mother’s milk. Overall, the more HMOs that were present, the more Bifidobacteria were present, and different HMOs seemed to be associated with different bacterial profiles.

Autran CA, et al. Human milk oligosaccharide composition predicts risk of necrotising enterocolitis in preterm infants. Gut. 2018;67(6):1064-70. Samples of milk being fed to VLBW preterm infants were collected, 10 of them developed NEC, 8 were stage 2 or 3. The milk they received prior to developing NEC had much lower concentrations of a specific HMO, disialyllacto-N-tetraose, compared to matched controls (5 per case). A few of the cases did in fact receive some formula (which you only discover by opening the supplementary materials), and I can’t see any mention of donor milk in the manuscript. The data do seem to suggest a fairly strong association between low maternal milk concentrations of this particular HMO and the development of NEC.

Meredith-Dennis L, et al. Composition and Variation of Macronutrients, Immune Proteins, and Human Milk Oligosaccharides in Human Milk From Nonprofit and Commercial Milk Banks. Journal of human lactation . 2017:890334417710635. Despite the title, this article is not really about the profit motive, it is about the composition of milk that came from 3 different sources, one the Mothers’ Milk Bank in San José, which uses standard Holder Pasteurization (62.5 degrees for 30 minutes), the second being Prolacta, which uses something called vat pasteurization (63 degrees for more than 30 minutes), and the 3rd Medolac, which uses a retort sterilization technique (121 degrees and 15 psi for 5 minutes). The group from UC Davis did extensive analysis of 3 samples from each source and found that the macronutrients were different: protein concentrations were highest with the Holder pasteurization technique (but the donor pool might have a few more mothers who delivered prematurely) and the fat content was lower with the retort sterilization.

For the immune proteins “The concentrations of IgA, IgG, and IgM were the lowest in the milk samples sterilized by the retort method (p < .05). Concentrations and abundances of lactoferrin, α-lactalbumin, α-1-antitrypsin, and casein (α, β, and κ) were the lowest in the milk samples that were sterilized by the retort method and highest in the milk samples pasteurized by the Holder method (p < .05).”

To return to the HMO topic of the day “The concentration of total HMOs was about 2-fold higher and approximately 50% higher in samples pasteurized with Holder compared with retort and vat methods, respectively (p < .05).”

You can’t ascribe all of the differences to the pasteurization/sterilization method alone, as there are other differences in sourcing and manipulating the milks that are different, but the milks were clearly not identical, and other studies also show that the treatment methods have differing, probably adverse, effects on milk composition.

This might, at least partly, explain why donor human milk doesn’t seem as good as raw mother’s own milk, as a prevention for NEC and sepsis.

To put all this together, prebiotic molecules, particularly specific HMOs, found in fresh maternal breast milk promote the growth of probiotic organisms in the breast milk. Together the probiotics and prebiotics in breast milk promote the development of a bowel microbiome that predominates in Bifidobacteria. Abnormal bowel colonization is commonly found in the very preterm baby, and some patterns, especially those lacking Bifidobacteria, are closely related to the development of late onset sepsis and NEC. Milk which is lower in some HMOs seems to be a risk factor for development of NEC. Maternal milk is quite variable in composition and microbiome, and some of that variability might mean that some mother’s milk is less protective than others. Donor human milk, has most of the microbiome destroyed (on purpose) and exactly how it is treated has differing impacts on composition, including on probably protective components. Further supplementation of maternal and donor human milk feeds with probiotics, prebiotics, and potentially other bioactive molecules such as lactoferrin is a reasonable approach. Probiotic supplementation is already shown to reduce NEC, and to a lesser extent late-onset sepsis, but many studies show a relatively modest contribution of administered probiotics to the preterm intestinal microbiome  We need to investigate supplementation of maternal (or donor) milk with prebiotics, particularly the right HMOs; we may be able to make human milk even more efficacious as a way of preventing these complications.

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