Not neonatology: Julian Bream 1933-2020 RIP

Posted on 17 August 2020 by Keith Barrington

Most of my readers probably don’t know that for a few years I have been struggling to learn Classical Guitar.

One of my inspirations is Julian Bream, who was fundamental in the UK in the recognition of the guitar as a genuine Classical Music Instrument. After I watched one of his performances on youtube 2 days ago I wondered if he was still alive, and discovered that he had died less than 24 hours previously. There is an obituary in the Guardian which describes his contributions to music.

Bream was a genius in his interpretations of early guitar music, and in particular his renditions of lute music that had been re-transcribed for the guitar. He then learned lute, and for a long period was recognized as the best lute player in the world.

I think he was at his best with the modern Spanish composers and also, in particular, with the Brazilian Heitor Villa-Lobos. Here he is with the Villa-Lobos preludes, out of order, of course, the prelude no1, the best known and my favourite, starts at about 2:48. The second starts at 6:35 minutes, and I think he plays it too fast, but that is probably jealousy!

Villa-Lobos was himself a guitar player and wrote some of what I consider to be the best modern guitar pieces. Only one of which I can almost play all the way through!

A part of Bream’s legacy is the many pieces for classical guitar that he commissioned from many leading composers, including William Walton, Michael Tippett, Malcolm Arnold, and Benjamin Britten. The Bagatelles for guitar by Walton are among the masterpieces of 20th-century guitar music; according to the story, Walton didn’t really understand the guitar and asked Bream to send him a chart to explain what the guitarist could do, and what stretches were impossible. The piece by Benjamin Britten even Bream acknowledged as being fiendishly difficult to play, almost too difficult even for him!

There is a great documentary about his life on Youtube which among other great moments shows him playing the lute for a Dowland song with the tenor Peter Pears (Benjamin Britten’s long time lover), improvising jazz guitar with a group in his apartment in London, playing and improvising in a group in India with Sitar and Tabla, playing the Britten Nocturne written for him, and playing with his friend and the other 20th century English Classical Guitar genius John Williams.

A boy from a poor “broken home” in London who affected the lives of millions.

Exactly the kind of thing that the bunch of seriously incompetent fools who are currently in power in the UK want to prevent. The most recent catastrophe of re-grading school leavers exam results (under cover of COVID) to give extra credit to the most privileged, and downgrade those who have struggled all their lives to overcome their disadvantages, will hopefully make voters in the UK sit up and take notice. The profoundly perverse tabloids in the UK, however, will, I am sure, try to pretend that this is all a communist plot!

Goodbye Julian Bream, bon voyage.

Posted in Not neonatology | 1 Comment

ELVIS is alive!

Posted on 17 August 2020 by Keith Barrington

I was searching through the lyrics of ELVIS songs for a quote that might be more apt for this new blog post than “It’s now or ever”, which I have used previously, when I realized that I am a loser, and I should spend more time with my kids!

The 2 year neurological and developmental outcomes of the ELVIS trial (Early vs Late Ventricular Intervention Study) have been published. Cizmeci MN, et al. Randomized Controlled Early versus Late Ventricular Intervention Study (ELVIS) in Posthemorrhagic Ventricular Dilatation: Outcome at 2 Years. The Journal of Pediatrics. 2020. Hopefully, you will remember (surely as a result of my previous ELVIS blog post) that this was a much-needed RCT comparing 2 strategies for intervening for post-haemorrhagic ventricular dilatation in preterm infants. You can imagine the importance of this study when you note that Linda de Vries, Floris Groenendaal, and Andy Whitelaw were all three involved in organizing and performing this trial. Post-haemorrhagic hydrocephalus (PHH, as I will call it from now on) has become less frequent over the years, as severe IVH has become less common, but it remains a major problem for a small number of babies.

In ELVIS, preterm infants under 35 weeks gestation who had an acute IVH with ventricular dilatation followed by progressive ventricular dilatation, were randomized to either of 2 approaches; in the early group:

treatment was started after the Ventricular Index had crossed p97 (97th percentile) but before crossing the p97+4 mm line, the Anterior Horn Width was >6 mm but <10 mm and/or the Thalamo-Occipital Distance was >25 mm. Intervention started with LPs (max 3), and if necessary, followed by insertion and taps from a Ventricular Reservoir, aiming for VI<p97 over the next 7–10 days.

In the late treatment group, the same sorts of interventions were performed, but they started when the ventricular index was greater than the 97th percentile + 4 mm, and the anterior horn width was over 10mm. This later threshold was based on old observational data, from Malcolm Levine I believe, that showed that once you passed this threshold progressive hydrocephalus was frequent. It had become a sort of default standard of care without any good data that it was the best indication for intervention.

In both groups, if a reservoir was inserted, it was tapped regularly

Ten mL/kg were removed once or twice a day, the volume adjusted according to cranial US. When taps from a reservoir were still needed 28 days after insertion to keep the ventricular index well below the p97+4 mm, one or two ‘challenges’ were performed with discontinuation of taps. Reservoir taps were resumed in case of expanding ventricles, clinical symptoms and/or excessive head growth. Taps were continued until infant’s weight reached 2000–2500 g and according to unit protocol, the protein had decreased to <1.5 g/L and erythrocytes <100/mm3, at which stage the infant became eligible for a VP shunt.

The primary outcome for the early phase of the study was whether or not you survived without needing a shunt.

As you might imagine, the early treatment group had many more LPs; and needed many more reservoirs, 40/64 compared to 27/62. They did not, however, need more VP shunts, in fact, slightly fewer shunts were needed with early treatment, 12 vs 14.

Of course what we really want to know is the long term outcomes, if they had been similar, then less intervention could be considered to always be a good thing, but if there was a difference between groups, then the increased need for intervention in the early group should be weighed against the outcomes. The 2 year follow up study analyzed outcomes from about 90% of survivors, so is a reliable indication of what outcomes to expect with these approaches.

Bayley scores were better with earlier intervention, and there was less cerebral palsy; there was a relatively small sample size, and therefore the differences shown may have been random effects. This figure suggests that, among those needing shunts, the differences were greater than could be expected by random variation.

Adjusted analyses showed that early intervention seemed to be associated with a decreased risk of an adverse outcome after correcting for gestational age, the severity of intraventricular haemorrhage and cerebellar haemorrhage (adjusted odds ratio: 0.24, 95% confidence interval [CI], 0.07 to 0.87. In this situation, I think adverse outcome means death, or cerebral palsy, or a Bayley version 3 motor or cognitive composite score more than 2 SD below the mean.

It is interesting that in the early treatment group 94% of the cognitive scores were above -2SD with early treatment, and 87% with later treatment. The large majority of preterm infants with PHH who were enrolled in this trial, therefore, did NOT have cognitive delay! There is obviously a great deal of selection that goes on before an infant would be randomized in a trial such as this, but good outcomes of PHH are not rare! Motor scores were more severely affected than cognitive scores, but were also somewhat better in the early treatment group.

The clinical implications of this trial to me are that PHH should be treated according to the early intervention thresholds in ELVIS. The differences in outcomes are not enormous, but all favour earlier intervention. The only advantage of waiting until the later thresholds are crossed is that there are fewer lumbar punctures and fewer reservoirs, but no reduction in permanent shunts. I also think the study confirms that the Levine thresholds from many years ago were reasonable, and, I think should now be considered to be late treatment. Once the late treatment thresholds are reached intervention becomes urgent and should not be further delayed, unless there is an understanding with the parents that interventions will be limited. If we are aiming for the best possible long term outcomes, then the early treatment thresholds of ELVIS should be followed.

Otherwise, we may be accompanying ELVIS singing “Maybe its too late, I sometimes even hate myself…”

Posted in Neonatal Research | Tagged , , , | 6 Comments

Does erythropoietin prophylaxis prevent NEC? Unreliable data.

Posted on 14 August 2020 by Keith Barrington

Routine erythropoietin administration from early life in very preterm babies has been postulated to be neuro-protective. Unfortunately, despite some early promising results, 2 large well-performed RCTs showed no benefit, including the largest with 750 babies under 28 weeks, which showed very small differences between groups and nothing that appeared to be a real effect of the erythropoietin.

Another trial of about the same size, but with less immature babies (800 of less than 32 weeks gestation) used a dose about half of those other 2 trials, it was published in Annals of Neurology for some reason. Of note, it was registered on clinicaltrials.gov after it was completed, and the registered primary outcome variable is MDI<70. Even though they registered the trial after they performed it, the published primary outcome variable is not the same, in fact, the published manuscript methods section does not mention a primary outcome variable, the results show in table 2 as “Primary Outcomes” 3 outcomes, Death, Disability, and Death + Disability. The sample size reported in the publication is 743, the registration document (submitted after the trial was finished) states the sample size is 490.  For several years the Annals of Neurology has required that RCTs are registered, that the registered primary outcome is the same as that reported by the article, and that the publication complies with CONSORT guidelines. Fail, fail, fail.

You might ask why I am spending so much time criticising a journal and an article when it was published in 2016? That article purported to show a substantial reduction in major intracranial haemorrhage with erythropoietin administration (EPO) from 16% to 7%, an enormous reduction in PVL from 20% to 11%, a reduction in sepsis from 26% to 20% and a lowering of “Death + Disability” from 27% to 13%. The Cochrane review of outcomes of early erythropoietin in preterm infants (which you can reach full text via the Vermont Oxford website https://public.vtoxford.org/cochrane-at-von/) is heavily dependent on that trial “Song 2016”. For serious IVH, for example, that trial contributes 73% of the weight in the analysis, for PVL it is 90%. If the data are unreliable, which I contend they are, then the systematic review is unreliable also. The Cochrane Systematic Review (SR) does not include the results of the most recent large trial Juul et al, as it was published after the SR was completed, and after the first author of the SR Arne Ohlsson sadly died, last year. That trial from the PENUT consortium showed NONE of those effects, no difference in IVH, PVL or sepsis or in developmental delay.

The Song 2016 trial is also the only trial in the SR that shows a reduction in NEC. As a result of only that trial the overall impact of early EPO appears to show a reduction in NEC. The same authors from Zhengzhou appear to have carried on with their same poor research practices, and immediately performed a subsequent trial (Wang Y, et al. Erythropoietin prevents necrotizing enterocolitis in very preterm infants: a randomized controlled trial. J Transl Med. 2020;18(1):308). Song 2016 enrolled patients until June 2013, (or perhaps January 2013 according to the registration document) the new trial using the same dosage regime (500 units/kg every 48 hours for 2 weeks) started recruiting in January 2014. Enrolment continued until June 2017 and the trial was registered 2 years later in April 2019. 1285 babies of less than 33 weeks gestational age were randomized. The primary outcome in the registration document is “Incidence of NEC” not further specified. In the publication which, strangely, has appeared in BMC Journal of Translational Medicine, the primary outcome is the same, but whether all grades of NEC or stage 2 and higher was the primary outcome is never specified.

If we concentrate on “confirmed NEC” as they refer to it, which is Bell grade 2 or higher, it is very frequent in this trial, 17% of the controls under 28 weeks, but the numbers of babies involved under 28 weeks is just 110 (53 controls and 57 erythropoietin). The incidence of confirmed NEC in more mature babies is also very high, at 30 to 36 weeks it is over 3%, compared to, for example, recent data from the Canadian Neonatal Network which shows an incidence of 1% at that gestational age.

Strangely, in both the new trial, and in Song 2016, the controls received a saline placebo, but the trials are reported as not being masked. I am not sure why you would go to the trouble of preparing and administering a placebo saline injection if the caregivers knew it was a placebo! Interestingly, the CONSORT flow chart shows that there were 1327 potentially eligible infants screened and only 20 refused consent, which is the highest consent rate I can remember seeing for a long time.

Mortality was 50/644 controls, and 34/641 EPO babies, which looks like a difference which is likely to be due to chance, but amazingly enough there is no statistical test of mortality in the manuscript, and compatibility intervals for mortality differences are also never reported.

What also surprises me about this article is the failure to report any other clinical outcomes. NEC and mortality are reported, but the outcomes that this group has reported previously as being reduced by EPO (IVH, severe IVH, PVL, sepsis, retinopathy) are nowhere to be seen.

The Journal of Translational Medicine is supposed to adhere to CONSORT standards, but they are woefully lacking in this publication. One might wonder why a multicentre clinical trial in preterm infants with major potential clinical importance was submitted to this journal; perhaps it was not the first choice, or perhaps the editorial standards suited the authors, the article was submitted to that journal May 20th this year, and accepted July 26th. Many open access journals publish the names of reviewers, and make available all versions of the article from initially submitted to final revisions, but BMC Journal of Translational Medicine does not.

The data in this publication are not consistent with the results of Juul, who showed a very minor difference in NEC incidence among infants who were all less than 28 weeks gestation; 6% with EPO and 8% in controls for stage 2 or 3 NEC. I discussed that high-quality trial previously https://neonatalresearch.org/2020/01/17/erythropoietin-for-brain-protection-in-the-very-preterm-not-worth-penuts/

This new trial creates a big problem for all of us interested in evidence-based practice. I think that the data are unreliable, but the sample size is so large that the results will overwhelm any attempt at systematic review of EPO impacts on NEC. Fortunately, there are few babies under 28 weeks, but even an analysis of EPO for prophylaxis of NEC among babies under 28 weeks will be heavily impacted because of the large number of events. I guess we can be grateful that all the other usual clinical three-letter outcomes were NOT reported! At least SR of early EPO impacts on IVH, PVL, BPD, RoP and sepsis won’t be impacted by the results of this trial.

Unfortunately, the same group appears to be continuing to perform their studies. There is another registration document on clinicaltrials.gov for a trial by this group (registered April 2016, enrolment was expected to start in May 2016 and be complete in December 2019) which is apparently underway. This, of course, overlaps with the trial just reported which finished enrolment in June 2017. In this most recent publication, they refer to the next trial as being among infants of under 28 weeks gestation, and examining retinopathy. In the registration document retinopathy of prematurity (not further specified) is listed as one of several short term secondary outcomes. The primary outcomes are listed as being two separate outcomes Mortality and the Incidence of neurological disability at 2 years old.

I for one won’t be giving routine EPO to my preterm babies to prevent NEC based on this data. For now, all that I think we can be sure about is that early routine EPO stimulates red cell production, which, depending on transfusion thresholds, is very likely to reduce blood transfusions. Any other potential benefits are unproven.

Prospective registration of RCTs has numerous benefits, including ensuring the completeness of the scientific record, ensuring that the analyzed primary outcome variables are those initially planned, and avoiding the addition of post hoc outcomes, unless they are clearly reported as being post hoc outcomes. Allowing publication of RCTs which are registered after they have been completed negates all those benefits, even when the authors still can’t get the sample size or the primary outcome correct!

Posted in Neonatal Research | Tagged , , , | 1 Comment

When should we transfuse preterm babies, and why?

Posted on 13 August 2020 by Keith Barrington

I was one of the investigators in the PINT trial (Kirpalani H, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr. 2006;149(3):301-7. that we published 14 years ago. That RCT found little difference in any clinical outcomes between higher and lower transfusion thresholds among 450 preterm babies with a birthweight less than 1kg. Of note, there was no difference in NEC or other typical neonatal complications. The follow-up portion of that trial showed no difference in the primary outcome, but there was a hint on post hoc analysis that perhaps the Bayley version 2 MDI was less likely to be below 85 in the liberal transfusion group.

The only other sizable RCT in the literature, until now, enrolled 100 babies < 1300g birthweight, and again showed very little impact (Bell EF, et al. Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants. Pediatrics. 2005;115(6):1685-91). That study was reported as showing a possible increase in the combined outcome of grade 4 IVH and PVL with restricted transfusion guidelines, but if you look at the results grade 3 haemorrhages were much more frequent in their liberal transfusion group (16% vs 2%) and if you examine all the significant brain injury together, there was no difference between groups.

Hence the need for more trials. At least 2 large multicentre RCTs have been performed, and the first to be reported is ETTNO (Franz AR, et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Extremely Low-Birth-Weight Infants: The ETTNO Randomized Clinical Trial. JAMA 2020;324(6):560-70). In this trial 1,000 babies < 1kg birthweight were randomized at less than 72 hours of age to receive transfusions when their hematocrit fell below either higher or a lower threshold. The thresholds were adjusted by postnatal age and whether the babies were “critically ill” or not. The schedule is here, and I am also including the notes, which describe the criteria for being “critically ill”.
If you are not used to thinking in haematocrit, just divide by 0.3 to get the approximate haemoglobin.

In general, I think this schedule is reasonable for an RCT; to be doable, a large multicentre trial needs to have methods to which enough people will buy in, and to be relevant, the criteria have to be applicable in future everyday practice, even if you are not sure that some of it makes sense. You could certainly criticize why babies in more than 25% oxygen on CPAP need to have a higher threshold than babies in 21%; the concentration of oxygen being inspired has no impact on tissue oxygen delivery. Also, higher thresholds for babies with frequent apnea or frequent hypoxic episodes could be questioned.

The primary outcome of the trial was “death or neurodevelopmental disability”, you can probably already hear me screaming! (Softly, into my coffee). The neurodevelopmental part of that is also referred to as “cognitive deficit”. The developmental part of the outcome, which is, as usual, the biggest contributor to the outcome, is based on a Bayley version 2 MDI score of <85 at 24 months corrected age. It is, of course, ridiculous to refer to a low score on a developmental screening test as an “impairment” or a “deficit”, especially when 1 SD is chosen as the cut-off, using this terminology 16% of all human babies are “impaired” or have “a deficit”. Combing a lowish score on a developmental screening test with death as the primary outcome is really lumping together 2 things that should clearly be evaluated separately. Neither of the previous trials showed any tendency to impact mortality, the primary outcome of this trial could easily have been developmental delay or neurologic impairment at 24 months corrected among surviving babies. Combing 2 outcomes of such disparate importance risks diluting the real importance of a trial, if mortality had by chance been slightly higher in one group than the other, then a difference in the important long term outcomes could easily be hidden, or all sorts of other possibilities arise. I don’t think there is any a prior reason why both mortality and developmental progress at 24 months should be expected to change in the same direction by this intervention. Mortality is so much more important than having a low-ish Bayley score that the risk of missing an impact on survival by including it in a composite with a much more common outcome is really quesitonable.

I think this would have been a good trial to analyze survival separately, and then to examine long term impacts on development and on neurologic dysfunction. But; to stick with the analysis plan of the published primary outcome, there was no apparent difference between groups.

More importantly, as survival was about identical, (91% restricted vs 91.7% liberal) and there was less than 10% loss to follow-up, we can have a great deal of confidence in the developmental outcomes which were close to identical between the groups. Mean Bayley 2 MDI scores 92.5 in each group with very similar numbers below -1SD and below -2SD, cerebral palsy and PDI scores similarly were not different between groups, and the more rare components of neurologic dysfunction (visual and hearing impairment) were also very similar.

As for shorter term outcomes they are listed in this table

You can see that there isn’t really a hint of a difference between the groups for any outcome. Also not in this table, but in another, the duration of respiratory support was identical, the age that caffeine was stopped was the same.

I think the complete lack of impact on NEC is a good sign that transfusion-associated NEC is a mirage. Twice as many low threshold babies as high threshold babies never had a transfusion (40% vs 21%), overall they received double the blood volume. The supplemental data show the average hematocrits in the two groups which are not enormously different, with few values being below 27, but there are large differences in the number of late transfusions between groups. NEC was also similar between groups in the two previous RCTs that I mentioned at the start of this post.

One concern about this otherwise excellent trial is that 25% of babies had already received at least one transfusion with packed red cells before randomization. That seems like an awful lot of transfusions in the first 72 hours, I guess that, being enrolled between 2011 and 2014, there were probably a lot of babies that did not get a placental transfusion, but it still seems like a high proportion of early transfusions in these infants.

The implications for clinical practice are that either of the transfusion schedules, or something in between them, are appropriate for extremely low birth weight babies and will not likely have an impact on short or long term outcomes. To make it simple (I like to make things simple) critically ill babies who have a risk of limited cardiac output responses to anaemia could have a threshold for transfusion throughout their hospital stay of a haematocrit of 34 (haemoglobin of 110 g/L) and stable babies the threshold could be 28 (haemoglobin of 90 g/L) in the first week of life, falling to a haemoglobin of 80 in week 2 and 3, and 70 thereafter.

 

Posted in Neonatal Research | Tagged , , , , | 4 Comments

Outcomes of infants born at 22 weeks gestation; attitudes are the best predictor of survival

Posted on 10 August 2020 by Keith Barrington

Among the most immature infants, mortality and morbidity are common even if they receive active neonatal intensive care, a new systematic review has attempted to find out how common. Backes CH, et al. Proactive Neonatal Treatment at 22 Weeks of Gestation: A Systematic Review and Meta-Analysis. Am J Obstet Gynecol. 2020. The authors of this study searched for publications detailing survival among infants who received active neonatal intervention. Sample sizes range from 2 to over 1,000, and definitions of what constituted active interventions varied between the component studies. The range of survival was between 0 and 100%, both of those extremes being from very small studies. As you can see from this figure, Ehret’s multicentre study contributed by far the most weight to the analysis, which overall shows somewhere between 1/3 and 1/4 babies survive with active treatment.

Ehret et al, the largest of the studies, with over 1000 22 weeks babies, showed that survival was 18% among the babies who received active neonatal care without the benefit of antenatal steroids, compared to 39% among those who received both antenatal steroids and active neonatal care. This systematic review confirms a higher survival at 22 weeks among babies who received antenatal steroids. It is possible, of course, that steroids are more likely to be given when other risk factors are absent and perhaps, therefore, are given to lower risk mothers; as observational data they cannot be relied on as absolute proof of efficacy. But it is also likely that when the Obstetric and Neonatal team have a positive attitude they are more likely to give steroids and intervene appropriately.

The difficulties that Carl Backes and his group had doing this study can be illustrated by the fact that the estimate of survival without moderate or severe developmental difficulties is 37%, which is higher than the estimate of overall survival, 29%! Clearly, this is because the studies evaluating development were taken from groups with higher survival. The quality of the data for the death and developmental delay outcome was very low.

A survival rate of somewhere between a third and a quarter is a baseline against which risk factors in addition to gestational age should be included (sex, estimated weight, chorioamnionitis), and, despite the group’s appropriate concerns about the quality of the data, it is a reasonable starting point from which to have conversations with prospective parents with threatened profoundly preterm delivery. If there is a possibility of active intensive care, then the systematic review confirms the value of antenatal steroid administration, which can be started immediately, and does not necessarily commit the team to active intensive care.

Travelling to centres with good outcomes among these babies, I am struck by the variety of clinical protocols and processes of NICU care, what the centres have in common is a positive attitude, that these babies can survive, even though mortality is high, and that a team approach with close collaboration with the obstetricians is key.

The attitude of Obstetricians around the world, and in the USA, varies from person to person and from perinatal centre to perinatal centre. But the attitude of the US obstetrics professional organisation, ACOG, as far as it can be gathered from their patient information page on their website /faqs/pregnancy/extremely-preterm-birth is very concerning, here is an extract:

What are the health outcomes for extremely preterm babies?

Medical advances have helped some preterm babies survive and overcome health challenges. However, the chances that a baby born extremely early will survive without disability are still small. With very rare exceptions, babies born before 23 weeks of pregnancy do not survive. Although survival rates increase for babies born between 23 weeks and 25 weeks of pregnancy, most survivors face serious, often lifelong disabilities. As gestational age increases, the outlook for preterm babies improves.

The copyright at the bottom of the page is dated August 2019. It needs an update! One in four is not a “very rare exception” and most survivors do not have serious disabilities, most have no, minor or moderate disabilities.

I think that active intervention at 22 weeks should not be universal, babies with additional risk factors may have a very low chance of survival, but this data confirms that survival rates that are a reasonable justification for active intervention are possible in more than one centre. Tertiary/quaternary perinatal centres should train and put in place procedures for active care of babies thought to be at 22 weeks, or be prepared to transfer mothers to centres that have a positive attitude and teams ready to actively intervene.

Posted in Neonatal Research | Tagged , , | 2 Comments

Omega-3 fatty acids, hype, and hope, and disappointment.

Posted on 7 August 2020 by Keith Barrington

Omega-3 fatty acids seem to be important for many functions, and currently many babies, especially preterm babies appear to be deficient compared to babies born at term. There has been much research into these dietary components, and they certainly are essential for normal cell membrane function and much else. The big questions are: how much do we need? Which ones do we need?

I even performed a study myself years ago among newborn piglets, we divided them into 3 groups who either stayed with the sow or were placed on intravenous alimentation with either regular intralipid or with a home-made mixture which included fish oil derived omega-3s. We showed a lower pulmonary vascular resistance among piglets getting the menhaden oil lipid (with extra omega-3s), which were similar to sow’s milk, they also had a more normal hypoxic pulmonary response, the intralipid piglets having exaggerated responses.

Many trials of supplementing these fatty acids, however, have been negative.

The most recent disappointment comes from the MOBYDick trial, a pan-Canadian RCT among mothers who delivered very preterm (23 to <29 weeks) and who were planning to give their breastmilk to their babies (Marc I, et al. Effect of Maternal Docosahexaenoic Acid Supplementation on Bronchopulmonary Dysplasia-Free Survival in Breastfed Preterm Infants: A Randomized Clinical Trial. JAMA. 2020;324(2):157-67). Nearly 500 mothers were randomized to a supplement of Omega-3 (DHA, docosahexaenoic acid) or placebo with the primary outcome being survival or needing oxygen at 36 weeks PMA. The trial was stopped early as a result of 2 things: interim analysis showed slightly worse primary outcome among the active treatment group; the N3RO study of postnatal supplementation of preterm infants was published showing somewhat worse bronchopulmonary dysplasia outcomes with supplementation compared to placebo
(Collins CT, et al. Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants. N Engl J Med. 2017;376(13):1245-55). In the N3RO trial 1200 very preterm babies (<29 weeks)  were randomized to daily supplements with omega-3s (60 mg/kg per day), the primary outcome was needing oxygen at 36 weeks. BPD by the physiological definition was more common with DHA supplementation than with placebo (49% compared to 44%), and there was no sign of any benefit.

The N3RO trial was itself performed as a follow-up to the DINO trial, also from Australia, which was an RCT among 657 infants less than 33 weeks who were randomized to get a DHA supplement, or just standard DHA intakes. Of note in that study the mothers all received a tuna oil supplement, and the preterm formula given if the mothers were not breastfeeding, contained the concentration of DHA then recommended. The primary outcome of that trial was developmental progress at 18 months, but the Bayley scores were just about identical in the 2 groups. One of the DINO trials secondary outcomes was oxygen requirement at 36 weeks, which was lower in the DHA supplemented babies (18% vs 25%), which I guess was one reason for performing the N3RO trial, among a group of babies at higher risk for BPD. Of note the DINO trial was reported, even in the abstract as showing that the supplement “did not increase MDI scores of preterm infants overall born earlier than 33 weeks but did improve the MDI scores of girls.” However, when I look at the results, there doesn’t seem to be a statistical test of interaction between sex and assigned group, they did note a small increase in Bayley MDI of 4 points in the girls, and a very small decrease of 1 point among the boys, in the contest of an overall 1.9 point difference, which was consistent with a chance difference. We need always to be careful with subgroup analyses. It would indeed be remarkable if the differences between intervention and placebo were identical between boys and girls (or between redheads and blondes for that matter). We should expect different subgroups to have different results, what is important is whether those subgroup differences are themselves consistent with random differences, or are they different enough to suggest a real difference in effect between the subgroups. A statistical test of interaction should be performed, not just looking at the p-values of the individual subgroup differences. There are some other indications of a possible small benefit of higher dose DHA though, which fewer infants below thresholds of 85 and 70 on the Bayley MDI scores, especially among girls, but with the same caveat. Subgroup differences should, generally speaking, never be taken as strong evidence that one group benefits and another does not, but can form the basis for further investigations focusing on the apparently better subgroup. Also of note, even longer follow-up of the DINO babies to 7 years of age (Collins CT, et al. Neurodevelopmental outcomes at 7 years’ corrected age in preterm infants who were fed high-dose docosahexaenoic acid to term equivalent: a follow-up of a randomised controlled trial. BMJ Open. 2015;5(3):e007314) did not show any benefit of the high-dose DHA, there was even a suggestion of harm with girls scoring higher (worse function) on some of the parental reported scores.

With the results from N3RO, the safety monitoring committee of the MOBYDIck trial did some calculations suggesting that it was very unlikely that supplementation would be found to be beneficial by the end of the trial, and, being worried that there might be harm, they stopped the trial, which had originally been planned to reach 800 mothers.

I was disappointed at the early stopping of the trial, given that the “harm” which worried the investigators was a slightly prolonged oxygen requirement, which doesn’t necessarily translate into any clinically important adverse impact, but I can certainly understand their motivations. Survival without BPD was higher among babies of mothers receiving placebo at 62% compared to 55% with intervention. Death was actually less frequent with supplementation 6% vs 10% by 36 weeks, but BPD was quite a bit more common 41% vs 31%. The authors never note the number of deaths prior to discharge, which I submit is much more important and relevant that death by 36 weeks, they note 2 deaths (intervention group babies) between 36 and 40 weeks, so I don’t think the final death comparison, if we knew how many died before discharge, is likely to be much different.  One can ask whether, by early termination of the trial, did they miss the chance of finding better clinically important longer-term respiratory outcomes, or developmental or visual outcomes? Probably not. Follow up of DINO doesn’t seem to show any distinct advantage of direct DHA supplementation, either on respiratory hospital readmissions, atopy, visual processing (including acuity), or developmental progress, or school-age IQ.

Gunaratne AW, et al. Docosahexaenoic acid supplementation of preterm infants and parent-reported symptoms of allergic disease at 7 years corrected age: follow-up of a randomized controlled trial. Am J Clin Nutr. 2019;109(6):1600-10.
Molloy CS, et al. Long-term effect of high-dose supplementation with DHA on visual function at school age in children born at <33 wk gestational age: results from a follow-up of a randomized controlled trial. Am J Clin Nutr. 2016;103(1):268-75.

Of note, treating preterm born infants with 6 months of DHA when they become toddlers also doesn’t seem to help them either (Keim SA, et al. Effect of Docosahexaenoic Acid Supplementation vs Placebo on Developmental Outcomes of Toddlers Born Preterm: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(12):1126-34).

And supplementing standard risk mothers with DHA during pregnancy doesn’t reduce preterm delivery. Makrides M, et al. A Randomized Trial of Prenatal n-3 Fatty Acid Supplementation and Preterm Delivery. N Engl J Med. 2019;381(11):1035-45.

So why all this disappointment? Maybe our babies are already getting enough, so even if intake and concentrations are low, they may be adequate for the majority of preterm infants. Maybe DHA by itself is not enough; Eicosapentaenoic acid (EPA) is good stuff too!FOr now, all we can say is that the new Canadian trial showed no advantage of maternal DHA supplementation, possibly a minor adverse effect on pulmonary outcomes, which is consistent with a minor adverse effect shown in the N3RO trial. No other good quality data show an advantage of maternal or neonatal supplementation.

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Screening for early-onset neonatal sepsis in the UK. NICE or not?

Posted on 4 August 2020 by Keith Barrington

Evaluating a screening procedure for a rare serious phenomenon, such as early-onset neonatal sepsis, is tricky. A perfect screening process would catch all of the cases that require treating at an early stage and would be completely specific, thus eliminating treatment of non-infected babies. Even ultra-rapid PCR of a blood sample, covering all known pathogens, would not be perfect, as it would probably identify many infants with transient low-level bacteremia…

Given that there will never be a perfect test, we should ask how many infants who are not ultimately found not to be infected are we happy to treat for each infant who has sepsis, and how many infants with sepsis are we prepared to allow to go without early treatment in order to avoid treating many uninfected babies?

This is a variant, I guess of the number needed to treat, and number needed to harm calculations that we are now used to.

What I mean is “are we prepared to miss one sepsis in order to avoid treating 100 healthy babies?” or should the number be 1000, or even more? Treating babies unnecessarily means painful investigations and treatment, potential complications of peripheral or central venous access, usually separation of mother and baby, as most hospitals don’t keep babies with IVs in routine post-partum rooms with the mothers, disturbance of the microbiome of the infant, leading to increased risks of late-onset sepsis and NEC among preterm infants, and possible increased obesity, increased allergic disease, and disturbed hypothalamo-pituitary-adrenal responses, in the long term among babies born at term.

On the other hand risks of mortality from unnecessary treatment are extremely low, compared to the risks of untreated sepsis.

There are a number of studies looking at large databases and noting the number of patients screened, and the number of truly infected cases found compared to the number of babies treated, in particular using new sepsis calculators. If early-onset neonatal sepsis is less than 1 case per 1000 among full-term infants (as it is in most parts of the developed world) then such results may not be able to answer the question about numbers if cases potentially missed with much confidence.

Another way to address the question is to come at it from the other direction and examine the history of babies who do indeed prove to be infected to ensure that the different approaches to screening would have required a screen and pre-symptomatic treatment. This new article attempts to do just that. (Morris R, et al. Comparison of the management recommendations of the Kaiser Permanente neonatal early-onset sepsis risk calculator (SRC) with NICE guideline CG149 in infants >/=34 weeks’ gestation who developed early-onset sepsis. Arch Dis Child Fetal Neonatal Ed. 2020:fetalneonatal-2019-317165). In 5 maternity units in the South-West of England and Wales, there were 70 confirmed early-onset sepsis cases in term and late preterm babies over various periods spanning 2008-2017. The total incidence was 0.5/1000 live births.

Of the babies with sepsis, 31 became symptomatic and were treated after 4 hours of age, and neither the Kaiser Permanente Sepsis Risk Calculator (SRC) nor the NICE (National Institute of Clinical Excellence) guidelines, largely followed in the UK, identified them as at-risk.

There were 27 babies for whom both the NICE guidelines and the SRC suggested screening and antibiotics.

The remaining 12 babies were recommended to have screening and treatment by NICE guidelines, but not by the SRC.

So if we imagine a region with 100,000 term and late preterm births per year, and 80 of those babies with early-onset sepsis. About 30 of them will have clinical signs early and will receive treatment under any scenario, all of the guidelines are directed at the other 50. From this study it seems that about 2/3 of that group do not have identifiable risk factors and are not treated either under NICE guidelines or using the SRC approach, they develop clinical signs later.

The remaining 16 babies (very roughly) have a risk profile that suggests treatment using NICE, but not when using SRC.

Previous guidelines (such as NICE) lead to about 20,000 of the babies being screened and treated, in order to cover those 16 babies during the asymptomatic period. Using the SRC reduces this number to about 4,000.

In other words, if I have my estimates somewhere near right, another 16,000 sepsis evaluations and antibiotic treatments are required to cover the 16 babies who are identified as being at risk by NICE but not by the SRC.

I think we should question whether 999 unnecessary sepsis screens and antibiotic courses are justified by 1 baby treated during the pre-clinical period; especially as there are twice as many babies who are asymptomatic who are not screened at all, using any standard, which means we must remain vigilant for the occurrence of sepsis in all newborn infants, and be ready to screen and treat when signs of sepsis develop.

Only one death was recorded in this study, among a baby who had clinical signs from birth, none of the babies treated after they developed signs at >4 hours of age died.

One thing that struck me was the enormous proportion of neonatal sepsis caused by Group B Streptococcus in this study, which was 90%. As a disease that has almost disappeared in North America, I don’t think the conclusions of this study, or the rough calculations that I did, can be translated directly to my practice. The total incidence of EOS in Canada is currently much lower than that reported in this paper, probably about 0.1/1000 among term and late preterm babies, about 50% of which are GBS (Sgro M, et al. Population-based study of early-onset neonatal sepsis in Canada. Paediatr Child Health. 2019;24(2):e66-e73). In other words, early-onset GBS disease is about 1/10 as common here as in the south-west of the UK. Time for universal GBS screening in pregnancy in the UK, anyone?

This study, although not directly applicable everywhere, does confirm that there will be a few babies with early-onset neonatal sepsis that develop clinical signs after the first few hours of life, that are not identified by current approaches before they become sick. But they are very few in number, which means that staying vigilant for signs of sepsis is vital for all clinicians caring for newborns. Dramatic reductions in unnecessary sepsis screens and treatments can be accomplished with a small risk that some truly infected babies will present and be treated later.

The NICE guidelines give an NNT of about 250 (20,000 screened for 50 babies with EOS without early clinical signs), compared to about 50 for the SRC. Each one of the extra 16 babies identified by NICE guidelines requires an extra 1,000 screens and treatments.

Which is a lot.

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RSV prevention, fewer jabs for babies?

Posted on 4 August 2020 by Keith Barrington

With all the hype regarding COVID-19 and a vaccine that may or may not be coming soon, we can use the story of RSV as an object lesson. Why do we give passive immunization to preterm infants against RSV rather than a vaccine?

RSV vaccines have been produced in the past, but there was significantly worse illness among babies who became infected despite vaccination. The vaccine was an inactivated virus but triggered “a nonprotective antibody response and CD4+ T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection”. Which is a phrase that I quote directly from (Acosta PL, et al. Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease. Clin Vaccine Immunol. 2015;23(3):189-95.) because I understand little of it, immunology was invented after I went to medical school.

Anyway, I can understand that under certain circumstances a vaccine could make things worse. As far as I can see, the trials in which the enhanced disease that occurred in vaccinated children led to the trials being stopped, and I don’t think a vaccine has ever actually been licensed as a result. Which makes me grateful for the FDA and other agencies around the world that require good evidence prior to the widespread use of a drug or vaccine. (In contrast to the claims of the antivaxers). So prior to rushing to introduce a vaccine for COVID-19 we need to be sure that it is safe and effective. Especially as severe cases of COVID seem to be associated with excessive immune responses, so there is a real possibility that a vaccine could make things worse at least for some recipients.

Newer candidate RSV vaccines will also have to be tested in adequate trials before we can be confident that they work and are safe. Vaccinating mothers is one possible way of getting around some of the problems, (Madhi SA, et al. Respiratory Syncytial Virus Vaccination during Pregnancy and Effects in Infants. N Engl J Med. 2020;383(5):426-39), However in this trial among 4,500 mothers who either received a vaccine based on the RSV fusion protein (F) or a placebo at between 28 and 36 weeks gestation, the overall reduction in clinically significant RSV disease in their infants during their first 90 days of life was from 2.4 to 1.5%. Which was not enough to conclude adequate efficacy, there were some signs of benefit, in terms of hospitalisations and severe disease, but not much more than about a 40% reduction for either.

For now then, I think we will be continuing with passive immunization while other candidate RSV vaccines (and there appear to be several) are being tested. Unfortunately that currently means monthly IM palivizumab injections at an exorbitant price, and a lot of discomfort. One improvement in passive immunization would be an antibody with a much lower clearance, such as this one (Griffin MP, et al. Single-Dose Nirsevimab for Prevention of RSV in Preterm Infants. N Engl J Med. 2020;383(5):415-25) so that a single dose would last the whole RSV season. In this trial, 1453 infants who had been born preterm (29 to <35 weeks gestation) but were not eligible for RSV prophylaxis according to their local guidelines were randomized to receive one dose of the new long-acting antibody nirsevimab, or placebo in a 2:1 ratio, if they were under 1 year of age at the start of RSV season. The primary outcome was the occurrence of RSV disease needing medical attention during the first 180 days, which was substantially reduced from 9,5% to 2.6%, and hospitalizations for RSV bronchiolitis were reduced from 4.1 to 0.8%.

I have little trust when it comes to big pharma, and I give you this prediction, that nirsevimab will cost substantially more than palivizumab. Probably the producers will calculate the average number of doses of palivizumab that babies receive (which is probably about 3.5) they will then price nirsevimab to be 3.5 times more expensive than palivizumab, so that they will be able to tell you that there is a substantial saving in resources with the new drug (which would be true), and a reduction in pain and discomfort, but they will still be able to screw our health systems for as much profit as they possibly can! I used to think that drug pricing was based on development and production costs, with a profit margin added; how naive! Drug prices are based on the principle of AMAWCGAW (as much as we can we get away with, ©Barrington 2020), and I can’t see AzstraZeneca and Sanofi Pasteur deviating from that time-honoured principle.

I would love to be proved wrong.

Posted in Neonatal Research | Tagged , | 3 Comments

Why are so many mothers hypothyroid, and what should pediatricians do about it?

Posted on 27 July 2020 by Keith Barrington

I don’t know if, like me, you are surprised by how often when admitting a baby, or doing an antenatal consult, mothers are taking thyroxine. It seems that there is an epidemic of hypothyroidism during pregnancy, and I am not sure what paediatricians should do about it.

A large proportion of these mothers were not on thyroid supplement prior to pregnancy, and seem to have so-called “sub-clinical hypothyroidism”. It is defined by a normal T4 with an elevated TSH and seems to occur with extremely high frequency, from 15 to 28% of all mothers in areas of the world where there is sufficient iodine.

I tend to have doubts about anything that occurs that frequently among otherwise healthy people as being a disease, it seems likely that, for most women with this “condition”, it is just a variant of normal, a review article from the BMJ from a few years ago (Wiles KS, et al. Are we overtreating subclinical hypothyroidism in pregnancy? BMJ. 2015;351:h4726.) stated the following:

 Evidence that this will cause adverse pregnancy outcome is inconsistent and conflicting. Equally, treatment with thyroxine has not been shown to be beneficial. While results of ongoing trials are awaited, thyroxine treatment is recommended in the absence of evidence of harm. However, the possibility of overtreatment in pregnancy should be considered. Monitor for iatrogenic hyperthyroidism with a repeat TSH four to six weeks after any change in thyroxine dose and be aware that most of these women will not need ongoing thyroid replacement after pregnancy.

I checked for recent systematic reviews of treatment of this and the latest ones that I could find include many observational studies, and a few small RCTs: the best SR, I think, includes only the RCTs, and is quite inconclusive (Yamamoto JM, et al. Impact of levothyroxine therapy on obstetric, neonatal and childhood outcomes in women with subclinical hypothyroidism diagnosed in pregnancy: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2018;8(9):e022837). There is possibly a reduction in preterm delivery, but the confidence intervals are wide and include a 21% increase in preterm delivery. Some of the observational studies seem to show a reduction in pregnancy loss, but the RCTs have not really investigated this. There is a possible increase in NICU admission among babies from treated pregnancies by 23%, but again confidence intervals are wide and include a reduction in NICU admission. The total sample size from the 2 articles that were meta-analyzed is only just over 1000, which is disappointing for a “condition” that is so incredibly frequent and should be relatively easy to study. The overall conclusion of the SR is “no evidence of benefit of levothyroxine therapy on obstetrical, neonatal, childhood IQ or neurodevelopmental outcomes. Current trial evidence does not support the treatment of subclinical hypothyroidism diagnosed in pregnancy”.

To return to my main question, if a baby is born after maternal thyroxine treatment during pregnancy, should the paediatrician (or family doc) do anything different for the baby?

In this study from Sydney the authors had noted that many babies were getting thyroid function screening, despite the presence of a universal thyroid screen (Churcher LM, et al. Reducing unnecessary neonatal testing in infants of mothers with thyroid disease. J Paediatr Child Health. 2020) they instituted a new guideline based on the most recent evidence which is summarized on a card including these major points regarding babies born from a mother who was getting thyroid supplementation:

  • Additional tests are very rarely needed
  • The only groups that need additional screening tests for the baby are:
    • Maternal thyroid disease with orbitopathy
    • Maternal past/current treatment of Graves’ disease (radio-iodine or thyroidectomy)
    • Maternal anti-thyroid drugs – Carbimazole or PTU
  • Even these babies only need additional tests if maternal Thyroid Receptor Antibody is positive or unknown
  • The Newborn Screen is enough for all others

After producing this they noted a dramatic reduction in unnecessary thyroid testing of newborns. Without having to argue with the obstetricians about the need for 1 in 5 otherwise healthy mothers to be treated with thyroxine during pregnancy, it appears to have no adverse neonatal effects and does not require further testing or treatment of the baby.

 

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One Million Page Views!

Posted on 27 July 2020 by Keith Barrington

I started this blog a few years ago as a replacement for my practice of sending an occasional email to local fellows and colleagues whenever I found an article particularly interesting or important. At the time I was thinking that it was worth the effort if there were 100 views per post. Well, nearly 900 posts later the blog just reached 1,000,000 page views! Thank you to all my readers.

I receive many positive comments from people around the world, which is gratifying, and despite a slow summer, for personal reasons there were no posts during June, the blog will continue as long as I have access to the neonatal literature and as long as I can think of comments that might help others. In the meantime, as a special treat for wildlife lovers, here are a few of my recent photographs.

This is a female Spruce Grouse that we surprised out foraging with her chicks, here is one of them: The day before, at the Cap Tourmente park, I noticed this purple finch

and a few minutes later on the feeders at the nature centre in the park, this Indigo Bunting arrived.

I have shown pictures from Cap Tourmente on the blog previously (see the Quebec Birds page under “Photos” from the main menu) it is best known for the huge flocks of Snow Geese that stop to refuel there during the autumn migration eating the rhizomes of the bullrushes. On this visit I was not expecting to see any as they pass their breeding season and summer in the high arctic, but there were a few around who had decided to stay in warmer climes.

Posted in Not neonatology | 7 Comments