As well as all the high tech mechanistic studies in NEC, such as those that I just posted about, sometimes we need to take a step back and ask some very basic questions. What is the current natural history of NEC? How good are we at diagnosing NEC?
So much has changed in neonatology since NEC was first described, that this new study from the Pediatrix database is timely, (Mara K, et al. Necrotizing Enterocolitis in Very Low Birth Weight Neonates: A Natural History Study. Am J Perinatol. 2022). It includes data from babies born 23 to 29 weeks GA who had a birthweight less than 1500g. The babies were divided into those with suspected, medical or surgical NEC. It shows a peak in confirmed NEC incidence around 2007, with a fairly marked decrease since then, being relatively stable since 2015. There has also been a switch in antibiotics used, with much more Piperacillin/Tazobactam, much less 3rd generation cephalosporins, and a drop in vancomycin use over the last few years. There has also been a switch from clindamycin to metronidazole for anaerobic coverage.
There is a huge amount of data in this publication, so I will just mention a few highlights. Risk factors for development of NEC are confirmed as being lower GA, male sex, small for gestational age and being outborn. Mortality is elevated, and is extremely high for surgical NEC: 6% for suspected NEC, 16% for medical NEC and 43% for surgical NEC. Positive blood cultures within 7 days of diagnosis were positive in 20%, and among surgical NEC were positive in 40%. Postnatal growth restriction was common among these babies, especially the surviving surgical NEC infants.
In addition to the obvious human costs of NEC the calculated additional financial costs are enormous. Length of stay was 26 days longer for confirmed NEC babies, and just on that basis average increased hospital charges are about $200,000 per case. Which can be calculated for the whole of the USA to be nearly half a billion dollars a year. That estimate does not include post-discharge costs, which are also enormously increased for NEC babies. Any intervention which has a reasonable cost and which decreases NEC will save money, as well as lives. Another good reason for funding NEC research!
The study has the advantages and limitations of a large database, meaning that individual diagnoses were not verified (of course) and we have to assume that these were all cases of NEC. That assumption is challenged somewhat by this meticulous individual examination of cases; BErrington J, Embleton ND. Discriminating necrotising enterocolitis and focal intestinal perforation. Arch Dis Child Fetal Neonatal Ed. 2022;107(3):336-9. By examining in detail the case records of babies in their local database, it was clear that differentiating the 2 phenomena is difficult, there is overlap in age of presentation, clinical signs at presentation, complications and outcomes. There is even confusion when the histology is examined. Only by really carefully examining each individual case were they able to come up with a final decision, and I am sure they would agree that other people examining the same cases might sometimes have different conclusions! Spontaneous intestinal perforation, with the typical anti-mesenteric perforation in the absence of skip necrotic lesions, has some aetiologic characteristics in common with NEC, but I think it is unlikely that interventions to prevent NEC will also prevent SIP.
The long term outcome impacts of NEC are well known, the data about SIP outcomes are more inconsistent, but there do appear to be substantial adverse impacts on neurological outcomes and on developmental progress. There are also major impacts of NEC on feeding and nutritional outcomes, and associations with lung injury and retinopathy and behavioural problems.
On this day we need more than just awareness, a co-ordinated effort to reduce the incidence and the impact of NEC, and SIP, will improve the future lives of thousands of babies and their families.
As we approach world NEC awareness day (May 17th) I thought I’d do a quick PubMed search to see if I’ve missed anything recently, so I started typing “necrotizing” in the search bar, which immediately suggested “necrotizing enterocolitis” as one of the possible completions, so I clicked on that and found there were 9,700 potential hits, ranging from the first reports in premature infants in the 1950’s, the first US series in 1964, and a progressive increase in annual publications to 766 last year. Apart from the odd report in animals or older patients, almost all of these publications are about neonatal human NEC, or animal models of neonatal NEC.
Recent work that caught my eye included the following, a study of the intestinal “virome” in very preterm babies. This was an “-ome” that I hadn’t come across before, but it was fairly obvious what it meant. (Kaelin EA, et al. Longitudinal gut virome analysis identifies specific viral signatures that precede necrotizing enterocolitis onset in preterm infants. Nat Microbiol. 2022;7(5):653-62) The authors identified a number of bacteriophages and what they call “eukaryotic viruses” which stumped me for a minute, as I was stunned that a virus could be a eukaryote; but of course a virus cannot be a eukaryote, the term refers to viruses which infect eukaryotic cells. Such as COVID, or all of the other viruses causing disease in humans. Not too surprisingly, the large majority of viral signatures that they found in the stools of preterm infants were unclassifiable. To be really honest, I don’t understand a lot of the analyses that they performed comparing the sequential viral and bacterial microbiomes of 9 preterm babies who developed NEC and 14, matched for GA and birth weight who did not. So, unusually for me, I will have to take them at their word that they found that “the viromes of infants who developed NEC converged towards a reduced level of beta diversity before NEC ensued and this convergence was characterized by specific viral signatures”. Of course this is a small series form a single hospital, and will need to be confirmed, but it suggests that viruses may have a role in the development of NEC, and specifically some bacteriophages may be implicated.
Goblet cells and Paneth cells were also impacted, as were intestinal permeability which was dramatically increased, and the antibiotics, not surprisingly, had major effects on the intestinal microbiome. When they got both antibiotics and then later Klebsiella, intestinal permeability was even further increased, TNF alpha and IL-1 beta also shot up, and half of the animals developed an intestinal injury which looks a lot like NEC.
Another fascinating study looks at whether using AI to interpret intestinal microbiome composition could possibly predict NEC (Lin YC, et al. Interpretable prediction of necrotizing enterocolitis from machine learning analysis of premature infant stool microbiota. BMC Bioinformatics. 2022;23(1):104), again I can’t pretend to understand a lot of what they did, but by re-analysing data from 2 prior cohorts of sequential microbiome analysis in preterm babies, among whom a number developed NEC, they were able to train an AI system to predict NEC. The system predicted NEC in the majority of preterm babies at birth, which isn’t very useful, but you could just ignore the first couple of days, and then as the days progressed there was a progressive divergence leading eventually to a reasonably good sensitivity of 86% and specificity of 90% for predicting NEC, which was possible 8 days prior to clinical presentation. This hold out hope that sequential microbiome analysis could eventually prospectively be fed into the machine learning algorithm and give you a weeks notice that a baby is going to get NEC. What you would do about it at that point I have no idea, but maybe you should block the toll-like receptor-4.
Improving gut colonisation with B infantis, and/or other organisms that reduce inflammation by interacting with TLR4, as well as potentially other mechanisms will probably reduce NEC incidence.
Speaking of which there is a new Cochrane review of synbiotics for the prevention of NEC which found 6 trials. Unfortunately 3 of them used inulin as the prebiotic part of the “syn-“, which is quite probably not the best prebiotic to consider, other oligosaccharides and in particular lacto-N-tetraose, are much more effective at promoting the growth of B infantis. The 3 small trials which used other oligosaccharides were of variable quality, and give no real confidence that the reduction in NEC that they showed is a reliable effect. Ongoing work confirms the probable importance of lacto-N-tetraose, such as this one (Wu RY, et al. Structure-Function Relationships of Human Milk Oligosaccharides on the Intestinal Epithelial Transcriptome in Caco-2 Cells and a Murine Model of Necrotizing Enterocolitis. Mol Nutr Food Res. 2022;66(4):e2100893.) which showed that mice which received one of 3 different human milk oligosaccharides were protected against NEC which occurred in the controls, induced by hypoxia, hyperosmolar feeds and lipopolysaccharide; but that the mechanisms of protection were different between the oligosaccharides. Lacto-N-tetraose appears to have been one of the most effective at reducing inflammation.
There is still so much to learn about this disease, and despite the many advances in neonatology over the years, progress in NEC has been slow; although probiotics reduce the incidence of NEC it still occurs, and still devastates some infants. Determining which probiotic is most effective, how to enhance efficacy with the most effective prebiotic/HMO, and what to do when early signs of NEC or of intestinal dysbiosis occur, are topics that require further investigation.
Human breast milk, when freshly expressed, contains all sorts of goodies, to use the technical scientific term. Many of which are adversely affected by standard pasteurisation (called Holder pasteurisation, which is very similar to what Louis Pasteur himself invented in the 1860’s). Holder pasteurisation entails heating the milk to about 63o Celsius and holding it there for 30 minutes, as far as I can tell, it is called the Holder method because of the process of “holding” the temperature stable for a period, but if that is wrong and someone called Holder should be credited I would like to know. I believe it is the only method used in human milk banks that follow HMBANA standards (or NICE standards or others internationally), even though it is no longer used much in the dairy industry, who use short term high temperature (72o for 15 seconds, or even for 5 seconds) processing instead. Other methods, including Ultra-High Temperature, high pressure processing, ultraviolet, and radiation treatments, can inactivate bacteria and other micro-organisms.
Holder pasteurisation has major effects on large molecules and less effect on small molecules (to over-simplify). So not much impact on oligosaccharides in general, but major decreases in immunoglobulins, various enzymes (e.g. lactoferrin), and larger hormones (adiponectin). Even some smaller molecules, such as insulin, are heat-labile and severely reduced by pasteurisation.
Occasional neonatal sepsis from bacterial organisms found in non-pasteurised maternal breast milk can occur, and even pasteurisation doesn’t kill everything, in particular spore-bearing organisms are resistant, which is why pasteurised milk is not the same as sterilised milk. Indeed contamination of pasteurised donor milk with Bacillus Cereus is a major reason for disposing of donated milk after pasteurisation, as it cannot safely be given to extremely preterm babies. In one recent study, the only culture positive organism after pasteurisation was B. cereus.
All forms of pasteurization, however, inactivate cytomegalovirus, and CMV from unpasteurized maternal milk is the major source of postnatal CMV infection in our patients.
There have been several publications recently about the importance of postnatal CMV acquisition in very and extremely preterm infants, the results of which are somewhat variable. I thought I would try to summarize what these recent publications tell us.
The most recent article is from Melbourne (Bimboese P, et al. Postnatal Cytomegalovirus Infection of Preterm and Very-low-birth-weight Infants Through Maternal Breast Milk: Does It Matter? Pediatr Infect Dis J. 2022;41(4):343-51) they followed very preterm (<32 wk) and/or very low birth weight (<1250g) infants of mothers who were CMV IgG positive. Just under half of the eligible mothers were antibody positive, and they were followed with breast milk and urine PCR for CMV. They eventually pared down the cohort to 58 babies, of 49 mothers, who were exposed to CMV PCR positive breast milk, and then compared the clinical course between those who became urine PCR positive, and those who stayed negative. The data are from around 20 years ago, for some reason, and at that time there was no human milk bank, so the babies received either fresh, refrigerated or frozen maternal breast milk, or formula, all of the babies received at least some fresh maternal BM.
“In total, 30% (8/27) of the CMV-positive infants were asymptomatic, 48% (13/27) mildly symptomatic, and 22% (6/27) severely symptomatic at the time of the first CMV-positive urine sample. Neutropenia was one of the most common presentations at the time of first CMV-positive urine (44%; 12/27), followed by respiratory deterioration (33%, 9/27; apnea (3), new CPAP requirement (1), new intubation (2), increasing oxygen requirement (7)). Nine of 27 infants had a partial or full septic workup”.
A much larger cohort of infants <1500 g birth weight was published in 2020, (Weimer KED, et al. Association of Adverse Hearing, Growth, and Discharge Age Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight. JAMA Pediatr. 2020;174(2):133-40) from the Pediatrix group; because it is from a huge database the case definition and the comparison group are not quite as clear-cut, cases were defined by those who had a positive CMV culture or PCR from blood, urine, CSF, or respiratory secretions after 21 days. If they also had a positive test prior to 21 days they were classed as congenital, but if they never had a test before 21 days they were considered to have postnatally acquired CMV (and then analysed as a separate subgroup to see if that changed the conclusions). If a baby never had a CMV PCR or culture they were considered negative. The major outcomes of interest were: a failed hearing screen, length of hospitalisation and growth, with BPD and NEC being important secondary outcomes. Each of the 273 postnatally acquired CMV babies was propensity score matched with a control. Babies with postnatal CMV were much more likely to fail their hearing test, much more likely to develop BPD and there was very little NEC.
Length of stay was longer in the CMV babies, and there were some relatively small effects on weight growth, but not length or head circumference.
Remember that in that study there would have been many babies who never had a CMV pcr, so the overall rate of breast milk CMV transmission cannot be calculated.
In contrast, pasteurisation of breast milk reliably inactivates CMV, and it doesn’t seem to make any difference how you pasteurise. Even a very short time, 5 seconds at 62O, is partially effective, (Bapistella S, et al. Short-term Pasteurization of Breast Milk to Prevent Postnatal Cytomegalovirus Transmission in Very Preterm Infants. Clin Infect Dis. 2019;69(3):438-44) and in that study they were able to pasteurise the milk daily, starting on day 4 postnatally using a system in the NICU milk kitchen, or even at the bedside. In this study they included infants of mothers who were CMV IgG positive, and then tested breast milk weekly. Breast milk was pasteurised routinely before being given to the babies unless CMV cultures of the milk proved negative. They ended up with 87 VLBW or very preterm <32 wk babies at risk of catching CMV from the breast milk, only 2 actually became CMV positive among the babies who received the short term pasteurised milk, whereas they had a historical control group of 83 babies who received raw milk, of whom 17 became infected. Although unfortunately not a randomized trial, this is certainly suggestive that this simple bedside method of pasteurisation can reduce, but not eliminate breast milk CMV transmission. This method has less effect on some large molecules, such as growth factors, but it probably has a major impact on Bifidobacteria, which are universally present in breast milk, are important for neonatal gut colonization and metabolism of oligosaccharides, and we should try and preserve if possible. I don’t know if there is any way to inactivate CMV without killing Bifidobacteria, but, if not, it warrants an RCT to determine if, in very preterm babies receiving CMV positive breast milk, there is an overall advantage of pasteurization or not.
In summary, somewhere around a quarter of very preterm babies exposed to CMV positive breast milk become infected, and the most extremely preterm babies are at much higher risk. The acute infection often presents with thrombocytopaenia, and sometimes neutropaenia, a sepsis like syndrome, respiratory deterioration, and apnoea. Postnatal, breast-milk acquired CMV, also appears to substantially increase the risk of failing hearing screening, likely to mean a real increase in hearing impairment. Breast milk acquired CMV also probably increases the risk of BPD, and, with, much less convincing data, perhaps increases retinopathy and NEC. Whether routine screening of breast milk for CMV, and some sort of pasteurization in selected cases is warranted, effective and safe is unknown.
One unanswered question I have, which is one of the reasons that I was reviewing this literature, is what about steroids? I have seen babies have very serious systemic CMV after steroids were given , but I struggle to find data about the impacts of steroid use on CMV infections in the preterm. Are babies who receive steroids and CMV positive breast milk at increased risk of serious CMV infection? Should we modify our decision-making in babies from CMV IgG positive mothers? If anyone knows any data about the issue, please let me know in the comments. A pubmed search using what I thought were the right terms came up with nothing relevant, and when I took “newborn” out of the search I had over 2000 hits!
The AAP issued guidance on probiotic use in the preterm infant last year in the form of what they call a “clinical report”, which I didn’t comment on at the time, I thought it might be a bit redundant as I have made my views pretty clear over the years. Unfortunately the AAP guidance was, in my view, based on a very limited and biased review of the available literature, comes up with recommendations which are really questionable, and continues to be challenged as more data accumulates.
Nothing in neonatology has been as extensively researched as probiotics. Somewhere over 12,000 preterm infants at risk of NEC have been randomized in trials so far. While it is true that trials are of extremely variable quality, from the poor to the exemplary, the overall quality of the evidence can be described as moderate to good. Of importance is that not a single trial has reported adverse outcomes as a result of probiotic use. Some have been null, some have been positive, but not one has been negative.
It seems to me that individuals and centres that have made the decision to not use probiotics seek to justify their decisions by invoking the “poor quality” of the evidence, whereas centres that have nevertheless introduced probiotics routinely see a fall in NEC incidence.
Even worse than the AAP statement is the press release that accompanied it, including a statement not found in the guidance document ” The most recent trials have not shown a reduction in NEC in those at highest risk”, which is just not true.
One of the problems with this literature which allows this type of interpretation is that many trials have not presented their data in a stratified fashion. In other words, the data have not been presented for babies above and below 1kg. Even though the mean birth weight of participants is about 1 kg; this allows the AAP to suggest that few babies under 1 kg have been studied, and efficacy in such babies is uncertain.
In reality, about half of the 12000 infants in the studies were <1kg, and there is nowhere any evidence of a differential effect based on body weight, indeed that would be weird. This would be the only intervention that I am aware of that works less well in higher risk babies than in lower risk infants.
In addition, the AAP statement suggests that centres that choose to use probiotics “should discuss the potential risks and benefits of this therapy with parents and should strongly consider a formalized informed consent process”, I will never be someone to suggest that we should not discuss the potential risks and benefits of a therapy with parents, but what risks does the AAP want us to discuss? Among the huge numbers of babies in RCTs, there were no reported risks, indeed an evidence-based discussion of the risks would go something like: “there are a few reported cases of sepsis with probiotic organisms outside of the trials, and there is no sign in any of the trials that the risk of receiving probiotics is more than the risk of not receiving them, all the evidence shows that the risk benefit of probiotic administration is heavily on the side of benefit”.
More importantly, why don’t the AAP suggest an informed consent process for those centres who don’t give probiotics? Surely, the evidence, which shows that giving probiotics containing B. infantis, or a mixture of Bifidobacteria and Lactobacilli, has benefits and minimal risks, should be discussed with every parent in every NICU, not just in those who give them, but even more importantly, in those who don’t. Shouldn’t every parent have the opportunity to ask for a treatment which has only shown benefit in RCTs?
I’m trying to think of a parallel, but I think that all other low risk procedures and moderate risk procedures are universally available, I don’t think there are NICUs that have decided to never give surfactant, or antibiotics, or CPAP. So the only partial parallel I can think of is for extremely high risk procedures, such as ECMO. If you are looking after a sick full term baby with meconium aspiration who reaches ECMO criteria and you are in a centre that doesn’t offer ECMO, would the AAP consider it OK to not discuss transfer to an ECMO centre? That only centres offering ECMO discuss the risks and benefits, and the others should just pretend that ECMO doesn’t exist?
An decision to cannulate for ECMO is of course extremely high risk, and warrants extensive discussion with parents, and if you are in a non-ECMO centre, then the discussion should also involve the risks of the transport, but if it is a reasonable alternative for the individual baby, then that discussion should always take place.
I am not sure if many centres really use a “formalized consent process” for giving antibiotics, or surfactant? Interventions for which the risk/benefit is often much more questionable than for probiotics.
To put it bluntly, the current AAP advice is that parents in centres that do not currently offer probiotic prophylaxis for NEC should have the evidence hidden from them, and there is no obligation for them to be informed. In 2022 that is unlikely to be a successful policy, I am sure that many parents in the USA search the interwebs when their baby is in the NICU, and especially those whose baby develops NEC are likely to find the NEC society web site, whose educational materials clearly state :
“There is also good evidence that giving premature babies probiotics reduces their risk of NEC and increases their chance of survival. Neither human milk nor probiotics can eliminate the risks of NEC”. And
“Are there any risks of getting probiotics? There are risks and benefits to every treatment. The benefits of probiotics include maintenance of healthy bacteria in the intestine. This is believed to help prevent NEC. In rare situations, probiotic bacteria can get into the blood and cause infections. If babies develop an infection in the blood with the probiotic bacteria, they are given an antibiotic to kill the probiotic bacteria. When this has happened, the infections have been responsive to treatment. Based on the literature, it appears that the benefits of probiotic administration outweigh the potential risks.”
In an excellent editorial accompanying that publication Mark Underwood notes that the AAP statement does not suggest a “formalized consent process” for other interventions that reduce NEC, unpasteurized maternal milk administration and banked human milk use, even though the small risks from those interventions are probably greater than the risks of probiotics. Of course, the risk/benefit ratio of fresh maternal milk, and supplementation with banked donor milk, are clearly in favour of their use, but that is also the case for probiotics.
I think the AAP missed an opportunity to advocate for the development of probiotic preparations that are of sufficiently high quality, with stringent quality control and safety data, they missed the opportunity to advocate for comparative trials, with individual or cluster randomization. There are still many unknowns with probiotics, and trials comparing different strains, and different combinations could have a huge impact on preventing this atrocious disease. I think that trials comparing a B, Infantis alone, to a B. Infantis in combination with a Lactobacillus, and perhaps to a B. Infantis and oligosaccharide combination (preferably with DSLNT), would have a chance of improving care of very preterm infants and reducing the terrible consequences of NEC.
May is NEC awareness month, and May 17th is NEC awareness day. With those dates in mind, consider supporting the NEC Society, an organisation which involves parents and professionals, with the overall goal to create a world without NEC. A worthy goal indeed.
A long long time ago, in a galaxy… actually quite near here, the idea of servo control of inspired oxygen was already in the air. At the time I first heard about it, the idea was to control FiO2 based on PO2 derived from electrodes on the tip of an umbilical catheter (paper from the mists of time… 1979), so you can see how old an idea it is! Other systems were developed which used transcutaneous PO2, and although the systems worked, there were the obvious limitations of using TcPO2. Now multiple systems have been tested to control FiO2 based on the pulse oximeter, different algorithms compared, systems that work with high-flow nasal cannulae developed, and even use in the delivery room during resuscitation had been trialled.
What will it take for this to become standard of care?
Most babies receiving oxygen have adjustments to their oxygen supply several times a day, this is usually triggered by alarms from the pulse oximeter, which have an enormously high frequency, one recent study, for example, noted up to more than 300 alarms per day, which leads to alarm fatigue and even important alarms being ignored or with very delayed responses. Babies as a result may spend substantial amounts of time below and above target ranges. In our unit, as in many others, we have a target range of saturation for most babies receiving oxygen between 90 and 94%, but we set the alarms 2% wider than that in order to avoid too many alarms. In addition, our oximeter monitors have an adaptive alarm system, so if they are just 1% outside the alarm limit they don’t ring for 60 seconds, at 2% they ring after 30 seconds, and so on, until they ring immediately if more than 5% outside the limits. Even with these approaches, the alarms are very annoying to parents, nurses, and I dare say babies (and to me!).
What we really need are systems which reduces the number of episodes of hypoxia and hyperoxia, and reduces the duration and severity of over and undersaturation when they occur. I am not sure if the most important thing is to reduce the total duration of hypoxia and hyperoxia, or to reduce the number of episodes of hypoxia and hyperoxia. It may be that saturations rapidly changing up and down are worse than persistently low (or high) saturations, even if the total duration is the same. Re-saturation after hypoxia is a potent source of oxygen free radicals, so my guess is, that for the same total duration of hypoxia, it would be less harmful to have one long episode of mild hypoxia, rather than 100 brief episodes with intermittent re-saturation.
Hyperoxia is bad for your retina and your lungs, and probably your brain also, but is a persistent slightly high saturation worse than a saturation that goes up and down to 99% then back to normal? There might be animal data out there that address the issue, but I don’t know them.
There are a number of complicating factors, in designing automated control systems. Much hypoxia is caused by apnoea, which won’t be affected by giving more oxygen! Post apnoeic hyperoxia is already a real problem, which probably often occurs when caregivers increase oxygen during apnoeic spells (partly because mixed and obstructive apnoeas don’t look like apnoea, so people try increasing the oxygen anyway). An automated system which routinely increased oxygen administration during apnoeas could be problematic. But, with the appropriate safeguards built into the algorithms it should be possible to safely reduce overall oxygen instability, and reduce alarms.
Another fairly trivial problem for an automated system, would be to turn off the high saturation alarm when the baby is in 21% oxygen, and turn it back on again when the oxygen concentration is increased; this is by no means a trivial problem in the NICU currently, babies in variable very low concentrations of oxygen who have a period when they saturate above 96% in 21% oxygen, will currently, appropriately, have the high alarm switched off by caregivers, and then when the baby needs an increase in FiO2 for a temporary desaturation, they often end up in low supplemental oxygen concentrations, with saturations above the desired limits and the high alarms turned off.
Two years ago Carlo Dani reviewed the then available literature, finding 16 trials which compared oxygenation outcomes between standard and automated oxygen control. He showed that overall the proportion of time spent in normoxia was increased, with less time spent hyperoxic, and a smaller impact on hypoxia, with automated control. Since then there have been several other trials published, including one by his own group, but we still don’t know if any clinical outcomes might be improved.
One of the outcomes that always seems improved in the trials, when reported, is the number of manual oxygen adjustments that were required, which is usually dramatically reduced. Alarm frequency is not something that I have seen reported much, but is presumably substantially reduced. One interesting study (Warakomska M, et al. Evaluation of two SpO2 alarm strategies during automated FiO2 control in the NICU: a randomized crossover study. BMC Pediatr. 2019;19(1):142) randomly compared 2 alarm strategies in a cross-over study, among babies who are all on automated oxygen control, they crossed-over babies who had normally a target range of 88-95% saturation, and had either alarm limits set to 87 and 96%, with a 30 second delay, or looser alarms, set 2% wider with a 90 second delay. They only studied 21 babies and started on day 1 of life for up to 6 days, and the alarm strategy crossed over every 24 hours, they used the Avea ventilator for both invasive and non-invasive support and stopped the study when they were off CPAP. Although the alarm limits were wider and slower, and therefore rang much less frequently in the “loose” group, oxygen saturation profiles were identical, being 95% of the time normoxic (88-96% unless in room air, when >96% still considered normoxic). The number of actual alarms is shown below.
The holy grail, of course, to use an overused metaphor, would be to show that automated servo controlled FiO2 decreased retinopathy and shortened resolution of lung disease. I guess equipment manufacturers would then charge enormous amounts of money for their systems, so maybe we don’t want that! Just making life easier for families in the NICU by reducing alarms, and making life easier for caregivers (mostly nurses) by reducing alarm fatigue, that should be enough to make automated control standard of care, but it will be hard to find the money to buy the systems unless we can show there are fewer complications.
One of the reasons for writing about this now is this new publication from the Pediatrix group (Srivatsa B, et al. Oxygenation factors associated with retinopathy of prematurity in extremely low birth weight infants. J Pediatr. 2022), in a retrospective analysis of oxygenation changes during ventilatory assistance, which was respiratory support of HFNC of 2 litres or anything more than that (CPAP etc.) whether or not the infants were getting supplemental oxygen. They included 101 ELBW babies who had at least 45 days of data during the first 2 months of life and survived to have an eye exam, from a single NICU, of whom 33 developed mild and 15 had severe RoP (6 needed treatment). They found the babies with severe RoP were exposed to higher FiO2 and had more frequent FiO2 adjustments compared with the group without RoP. Room air hyperoxia (>95%) occurred more frequently in the group without RoP whereas iatrogenic hyperoxia occurred more frequently in the group with severe RoP. Babies with severe ROP had more hypoxic episodes and a longer time spent in severe hypoxia (<80%) than those without ROP. You would hope that reducing those fluctuations would reduce RoP, but of course, you can’t be sure of that from an uncontrolled observational study like this.
A recent pre-post study (Salverda HH, et al. The effect of automated oxygen control on clinical outcomes in preterm infants: a pre- and post-implementation cohort study. Eur J Pediatr. 2021;180(7):2107-13) was unable, however, to show a benefit of automated oxygen adjustments, they analyzed cohorts of 24 to 29 week gestation babies over about 3 years before and 3 years after routine use of automated oxygen adjustment. The babies in the cohorts look quite similar in terms of risk factors, during the after period, duration of intubation and CPAP was less, and HFNC was more, but that might of course have nothing to do with the O2 system. Rates of retinopathy were low and stable, and there was a bit more severe BPD and a bit less moderate BPD after implementation, but that could easily just be due to practice patterns changing and the use of HFNC, which tends to inflate rates of diagnosis of severe BPD (more about that another time!)
Showing a reduction in RoP, for example, when only 10% of the eligible babies develop the condition, and only half of them need treatment (as in these cohorts in Salverda et al) will need a very large trial. Which is why I am grateful that an international European collaborative will enrol over 2300 babies <28 weeks.
But, as I already mentioned, even if there is no improvement in clinical outcomes, as long as they are not worse, I think there are major benefits to families of having fewer alarms, and, if I had access to devices to fit to my ventilators/CPAP/HFNC devices right now, I would do so.
I was disappointed to not be able to go to PAS this year, mostly because I am privileged to have a circle of former trainees, colleagues and friends from around the world who are all involved in trying to improve care for newborn infants. I love meeting up with you all every year, and after the pause caused by COVID it would have been great to see so many of you. Still someone has to look after the babies. I decided to give myself a reward and go on a birdwatching trip on Monday, travelling to Baie du Febvre, on the St Laurence about half way between Montreal and Quebec. It is one of the staging spots for the Snow Geese on their return from the south as they head to colder climes. In addition to about 10,000 Snow Geese I was pleased to run across this fella
He seemed to want to pose for his portrait, so I got my first ever shots of a Snowy Owl. Then he decided to fly off just as my memory card was getting full.
In addition there were a few purple martins, who come back earlier every year with climate change, and many tree swallows, like this one, who are building nests as they prepare for egg-laying
Other recent firsts for me were a Barred Owl at the Montreal Botanical Gardens
And Sandhill Cranes singing to each other (not very musically)
They stand about 1.5 m tall when they stretch their heads up like that, towards the other end of the scale is this Brown Creeper, about 12 cm from tip of beak to end of tail
Maybe next year after PAS I can post some selfies with my buddies!
The scientific basis of neonatology is vitally important to me, the enormous advances that we have made have all been founded on basic and clinical science. So I can get quite agitated when I see articles reporting trials of interventions for which there is no rational scientific basis, especially when they are published in reputable journals. This study for example in the Archives of Disease in Childhood, investigated whether osteopathic manipulation would improve the frequency of exclusive breast feeding. (It didn’t) If you don’t know much about osteopathy, maybe that would sound reasonable, but osteopathic manipulation is a practice with no scientific basis.
Osteopathy was invented in the 1870s by a charlatan called Andrew Still, who pretended to have medical training, and came up with vague beliefs that all human illness could be treated by manipulation adjusting the nerves and muscles. He reported his own forays into treating children, including a comment in his biography that he could “shake a child and stop scarlet fever, croup, diphtheria, and cure whooping cough in three days by a wring of its neck”. The scientific underpinnings of osteopathy have not advanced since then.
One could ask, for a study such as the one I opened the post with, if performing a negative study is a good thing, as it might convince people not to have their babies manipulated. Perhaps well-performed studies in countries where a lot of people already use osteopathic practitioners might be a good way to guide people away from them. I think that is extremely unlikely to be effective, despite the complete lack of a scientific basis for the practice, many people consult osteopaths, and I think recent experience has shown that regardless of how ridiculous the quackery you can find people defending it with very loud, effective pulpits on social media. I think, in contrast, performing such studies gives a veneer of scientific credibility that is unjustified, it is better to say from the start, that osteopathy is a practice based on the pre-scientific notions of a 19th century charlatan, and it should not be given any credibility.
If you want to see how ridiculous this continues to be, watch a few youtube videos from proponents of osteopathy. Apparently osteopaths are able, by touching a baby, to determine if there are abnormalities of CSF circulation, (there always are) and fix the circulation by laying their hands in various positions and by pressure or traction create permanent readjustments. They seem to be heavily into craniosacral pulsations, which apparently have a frequency of between 6 and 14 per minute, and are imaginary, of course, but any osteopath able to pay their consulting room rent will reliably find abnormalities of the craniosacral mechanism and fix them with manipulation.
It was very easy to find promotional videos which show how an osteopath would manipulate a baby’s skull to adjust the parietals and occipitals (they tend to know a lot of anatomy words) to cure colic, one of them used a pleasant circular rocking technique, which looks like it would make the baby temporarily calmer, but create permanent physiologic changes, I doubt it.
A quick word about D.O. training in the USA, which is quite different to what osteopaths learn in the rest of the world. In general in the USA D.O. trained physicians go to accredited schools, with the same accreditation as for M.D. training, and they have licences and scope of practice identical to MDs. Their training is just about identical also, with maybe some extra emphasis on the muskuloskeletal system, but that is not what we see in Europe, or Canada, where osteopathy practitioners have no relevant medical training.
Unfortunately the Journal of Osteopathic Medicine has its own youtube channel, with instructive videos about, for example, how the Galbreath technique of skull manipulation is supposed to permanently adjust the drainage of the Eustachian tubes and treat otitis media. Otitis media is over-diagnosed and over-treated with antibiotics, probably, anyway, so perhaps a bit of placebo manipulation might not be a bad thing! (That is a light-hearted comment, evidence-based otitis media evaluation and treatment is important). But when we come to infants, being treated for real problems where effective therapies exist, using ineffective manipulations or treating imaginary problems will not improve their health.
This amazing example (Osteopathic manipulation improves cerebro-spanchnic oxygenation in late preterm infants) was published in the journal “Molecules” which is a journal from MDPI, previously listed as publishers of predatory journals in Beales’ list: in this study the authors placed cerebral and splanchnic NIRS sensors on 7 day old late preterm infants, then performed manipulations while watching the NIRS signal. Regional splanchnic saturation decreased and calculated oxygen extraction increased while they messed about with the babies. They interpreted this as a good thing! Will you tell them or shall I? I think they should ask for a refund of the 2,300 Swiss francs they seem to have paid to get it published.
But it can get worrying, a prospective trial of osteopathic manipulation in asphyxiated babies post cooling was performed, in a hospital in the USA, one of the authors is from the hospitals “manipulation service”. Each of the 12 carefully selected enrolled babies was compared to 3 historical controls; even with this piss-poor study design they were unable to show any effect on length of stay, which was their outcome. But, low and behold, they did show that “by the final treatment, the craniosacral mechanism’s intraosseous and cranial base compressions and physiologic motion were improved”, so that’s good.
The authors also claimed that although there was no statistically significant difference in length of stay (9.1 days vs 10.1 days) it might be “clinically significant”. Fortunately this drivel was published in a journal called ‘the Journal of Osteopathic Medicine” so probably no-one will take any notice of it. How is it possible, that these authors, 2 of whom seem to have appointments at Tuft’s, can really believe that by touching a baby they can determine the intraosseus craniosacral mechanism, and its physiologic motion? It must take a special kind of self deception to swallow this stuff.
A “scoping review” of osteopathy (Osteopathic Manipulative Medicine, OMM) in paediatrics was published in the journal “Pediatrics” last year. They were unable to find any reliable evidence that OMM is of any value. The review concluded that:
“There is little strong, scientific, evidence-based literature demonstrating the therapeutic benefit of OMM for pediatric care. No strong clinical recommendations can be made, but it can be medically tolerated given its low risk profile. High-quality, scientifically rigorous OMM research is required to evaluate safety, feasibility, and efficacy in pediatrics.”
No, no, no. The first sentence is a bit weak, but truthful. The second sentence should be “There is no rational scientific basis for any of the claims of OMM”, and the third “It would be a waste of resources and an abrogation of our duty of care to families to perform more research of OMM”. If future research can find a hint of a scientific justification for osteopathy, then prospective randomized trials could, theoretically, be designed which should be carefully masked and use sham manipulations in controls. But the science should come first, which is currently lacking, craniosacral pulsations anyone?
Just after I pressed “post” for a recent addition to the blog, I saw this appear. (Callahan KP, et al. Influence of Genetic Information on Neonatologists’ Decisions: A Psychological Experiment. Pediatrics. 2022;149). It illustrates some major problems in how neonatologists react to genetic information. The authors questioned a national sample of neonatologists about how they would react to some genetic information. The respondents were randomized and each received 4 clinical vignettes, either with or without some genetic information, the cases were designed to illustrate real dilemmas that we face in clinical practice. One case that was really concerning was concerning an extremely preterm infant with an unusually protracted resolution of his lung disease in whom whole exome sequencing had been performed, in one version of the case there was no diagnostic abnormality, in the other the sequencing revealed homozygous abnormality of uncertain significance in a surfactant protein gene.
I would have thought that a finding of “uncertain significance” should have no impact on treatment approaches or goals, but that is not what was found.
For this scenario, that figure shows that neonatologists who got the information that there was a variant of uncertain significance (“Genetic”) were more likely to desire palliative care, and less likely to recommend invasive interventions than those who were told the WGS was normal (“Not Genetic”).
My interpretation of the finding is that many neonatologists do not understand what a variant of “uncertain significance” means, and that we are in need of education.
The American College of Medical Genetics classifies genetic variants into 5 groups: pathogenic; likely pathogenic; of uncertain significance; likely benign or benign. The terminology “variant of uncertain significance” is used for situations where the variant is either previously unreported or there are not enough cases to know what the impact might be. Sometimes the genetic geniuses can guess that, for example, a mutation which leads to an early stop codon, in an essential gene with other known diseases associated, is likely to be pathogenic, even if it has never been seen before. But a variant of unknown significance could easily be a mutation with no clinical impact at all. Surely a variant of uncertain significance should have no impact on decision-making.
The discussion of this case is very illuminating : “For this case, respondents cited pain and suffering as more important considerations if they saw the genetic version of the case and were thus more likely to recommend palliative care. There is no reason to believe that a VUS would be associated with increased pain and suffering. This pattern is in line with previous work documenting that physicians cite quality of life more often when recommending palliative, rather than invasive, interventions. It is also consistent with reported use of suffering to represent the general utility of an intervention and justify a wide variety of decisions.”
That is certainly also my experience, when neonatologists think that we should continue intensive care we talk about chances of survival and long term outcomes, when we want to limit care we start talking about suffering. I don’t understand though why a VUS (variant of unknown significance) would have any impact on those considerations.
In another of the cases there was an incidental finding of William’s syndrome in an extreme preterm baby at 2 weeks of age with septic shock and severe respiratory failure, the “control” non-genetic version stated that the genetics test was normal. The baby needed a central catheter inserted for antibiotics. I would hope that, if that happened in real life, the neonatologist, if unaware of the real implications of William’s syndrome, would consult colleagues and discover that William’s syndrome is a condition with variable and relatively mild intellectual impairments and a range of other moderately serious medical problems. I would not have thought that many people would consider William’s syndrome an indication for limitation of care, but the responses to this case were similar to the first, and the graphic is almost identical, substantially more neonatologists would recommend palliative care if the genetic abnormality was diagnosed, than those who had the case scenario with a normal genetic test, and fewer would recommend having a central line inserted for the antibiotics. I find it disturbing, that a diagnosis of Williams syndrome, even in an extremely sick baby, would lead to a recommendation to not even insert a central catheter for antibiotics.
Genetics is a discipline that has advanced enormously since I was trained, and the advances seem currently to be exponential. It is not surprising that there is limited knowledge among neonatologists of what the implications of certain findings might be. It is incumbent on us to seek out those who really are knowledgeable if we get back a genetic test result that we are uncertain about, and certainly not make life or death decisions that are not rational, and are based on misunderstandings.
To return to a concern expressed in a recent blog, there are animal models and some observational data that suggest that antenatal steroids (ANS) could have a negative effect on cerebral development, at least with the doses used currently. Among very preterm infants this is probably overshadowed by the positive effects on survival, early neonatal adaptation, and reduction in intraventricular haemorrhage. But when the benefits are more modest and short term, one might ask if the risk/benefit is positive.
Almost all of the data are from observational cohort studies, and almost all of the data for infants born at term are from a single study, which I have mentioned previously, Raikkonen et al. Which means that the conclusions of the SR and meta-analysis are identical to the conclusions of Raikkonen.
At the very least, this analysis shows we must get better data. With so many babies exposed to ANS who later deliver at or near to term, if there truly is an adverse effect it is essential that it be accurately quantified. The modest benefit of ANS for late preterm deliveries, with an absolute reduction of 3% of babies with respiratory distress, coupled with the worrying data in this systematic review, also make it clear we should improve our efforts to focus ANS use in women who actually will deliver very preterm. For babies who do eventually deliver very preterm, the advantages, both in the short term, and as shown in this publication, in the long term, are clear.
Annie Janvier, John Lantos and I have just published an article about Next Generation Sequencing (Janvier A, et al. Next generation sequencing in neonatology: what does it mean for the next generation? Hum Genet. 2022), which is a common way of referring to rapid whole genome or whole exome sequencing. We hang the discussion on 3 cases from the NICU at my hospital, which all had certain similarities, they were term newborn infants with unexplained refractory seizures. In each case rapid next generation sequencing (NGS) was organised, and took 5 to 7 days to have a result. We did not have access to ultra-rapid sequencing, which, in some publications, can have a turn around time of about 72 hours. In all 3 of our case histories the NGS gave a result of compound heterozygosity of probably pathogenic abnormalities affecting a likely responsible gene.
Our discussion is focused on the following considerations: 1. A small minority of NICU patients have uncertain diagnoses; 2. among babies with uncertain diagnoses, a minority have a diagnostic finding on NGS; 3. among babies with a diagnostic finding, a minority have an impact of NGS on their therapy; 4. among babies with an impact of NGS, a minority have a therapeutic intervention that will improve their condition. Which might all sound like we are Luddites fighting against the inevitable, but each statement is based on evidence from the literature.
Most babies are in the NICU because of prematurity, sepsis, asphyxia or major congenital anomalies. Only the last of those are sometimes monogenic, as well as some of the remaining infants with, for example, unexplained hypotonia or seizures or multiple minor anomalies. In large published cohorts it is often not clear what the denominator was, in one study from the Netherlands, NGS was considered appropriate in 2% of babies admitted to the NICU.
The proportion of babies with a positive, possibly diagnostic, finding on NGS, among those considered for testing, is between 19% and 51%. It will obviously depend on the threshold for testing, if testing is applied more widely the proportion with a possibly diagnostic finding will fall. But the proportion with incidental findings will be stable.
In how many babies does a diagnostic finding have a useful impact on their clinical management? This question was the hardest to answer from our literature review, as the reported impacts on management, and how they were defined were often unclear. Very often, the purported benefits were very questionable such as “referral to an endocrinologist” or “prescription of salbutamol”. Some of the rationales smacked of genetic determinism, for example a case where a supraglottoplasty was avoided because the precise variant associated with the infant’s CHARGE syndrome was discovered. I don’t know about you, but I wouldn’t have a supraglottoplasty performed, or not, based on the genetic rearrangement, but on whether that individual child had airway obstruction likely to be improved by surgery. Two infants with identical genetic abnormalities may have very different phenotypes, which has been shown many times, even in cases of mono-zygotic twins with CHARGE.
Among those with a medically actionable genetic abnormality, it is an even smaller proportion who have a condition for which specifically tailored or curative treatment exists for the condition diagnosed. We found, for example, cases in the reported cohorts of Dravet syndrome and of hyperoxaluria where therapy was changed after NGS, but even those specific examples are cases where other children have been effectively managed without NGS. Which isn’t to say that there were no benefits of NGS, just that a more rapid diagnosis and tailored therapy should be balanced against the cost implications, and also any potential adverse impacts.
One of the most commonly reported “benefits” of NGS in the NICU is a recognition that a condition is uniformly lethal or refractory to treatment, leading to a redirection of the goals of care, with the suggestion that this can occur more rapidly when there is an NGS result. In contrast, we think that caregivers and families may become unwilling to withdraw life-sustaining interventions without the NGS results, which may well lead to delays in redirection of care, and periods of unnecessary NICU treatment. Unless you have the enormous funding required to perform ultra-rapid NGS on demand, then a delay of at least 5 days is likely; even with ultra-rapid NGS this will likely be 72 hours minimum. As the majority of NGS results do not produce an aetiologic diagnosis, it could well be that the most frequent result of performing NGS is a delay in the withdrawal of life-sustaining interventions.
Very often, in the published case histories that we tried to analyse, it did indeed seem that performing NGS just delayed withdrawal of such interventions when it was clear that it was already something that should be considered. Obviously the brief details in a publication covering multiple cases cannot convey the complexity of the interactions of the medical team and the family, but our own experience, as described in our cases, illustrates that as something that can occur. One of our cases developed an iso-electric EEG during the interval between sending the NGS and receiving the result. We could have, and some families would have requested, waiting until the result was available, our evaluation of the situation was that there were no diagnostic possibilities that could lead to a good outcome and the medical team and parents agreed to redirection of care without the NGS result. In our estimation, that case was actually one where the NGS was helpful, just not in a way that would have been considered in any of the published cohorts. The parents were very relieved that the diagnosis was found, which reduced their feelings of guilt, and allowed them to adapt.
Another of our cases had a very different result, with an NGS finding of a condition that would likely lead to profound intellectual limitations and behavioural problems, for that case the parents stated that knowing the results had seriously adversely impacted their ability to adapt as new parents. The third case had a sort of neutral result, the parents were content to have a diagnosis but it made no difference to them regarding how they wanted their infant treated.
All of the cases in our article had a result from the NGS that was considered to be “probably pathological” affecting genes known to be probably implicated. We selected those cases to make important points for our discussion, but they represent a small minority of NGS results. Much more commonly NGS does not provide a diagnosis. Also very commonly NGS results reveal possibly pathogenic abnormalities, or abnormalities “of uncertain significance”, which may make decision-making more difficult rather than more straightforward. In addition, there are, of course, the incidental findings of abnormalities in other genes that may have clinical significance for unsuspected conditions. About 5% of NGS in children, for example, reveals cancer susceptibility genes, which may be of benefit for the future of the child, but very often the benefit is currently unclear, and balancing adverse impacts have not been considered.
I was surprised recently to see a debate in the BMJ, with pro and con articles regarding the idea of universal whole genome sequencing as a possible new standard for neonatal screening. Even though the pro position did introduce some nuances, and suggested a progressive revealing of results of Whole Genome Sequencing according to which results an independent panel would consider relevant at different ages, it still seemed to me to be motivated by the kind of genetic determinism that I mentioned above. The authors seem to believe that a genetic abnormality equates to the diagnosis of a disease state, and that revealing a diagnosis will improve health outcomes. Let me give you one counter example, discussed by John Lantos in his article The False-negative Phenotype. This is an example for just one genetic anomaly, Krabbe’s disease, in which universal screening in New York state commences with a screen for the metabolic abnormality (low galactocerebrosidase levels), and, among those who are proven to have the biochemical abnormality, then sequences the gene responsible. Ninety percent of babies who are identified as having both the biochemical abnormality and the genetic defect remain asymptomatic. This disease was previously thought to be just about universally lethal, but with screening we now know that is not true. It is also unclear how many babies without the biochemical abnormality have the gene defect; so what should we do when a baby is identified as having the genetic abnormality that causes Krabbe’s disease? There are many other examples (perhaps none so striking) of genetic abnormalities which are thought to be clearly pathogenic being discovered in individuals who do not have the disease thought to be caused by that abnormality, some other examples are discussed by Dr Lantos in that article.
The pro article in the BMJ does not mention that as a concern. They also state that “extensive clinical evidence has shown that screening for genetic diseases saves lives. Research has shown that it can be cost effective”. Those 2 assertions should be challenged, In answer to the first assertion, yes, screening for phenylketonuria saves lives and brain cells, screening for cystic fibrosis improves pulmonary outcomes, many other examples are available, but neither of those examples rely on genetic screening, they actually rely on detecting the presence of the disease, which, I reiterate, is not the same as finding the presence of the genetic anomalies. In support of the second assertion they reference an article which does not support their assertion! The referenced article in question models the cost-effectiveness of informing patients about a series of 56 incidental findings which the College of Medical Genetics in the USA recommend informing patients about if they have genomic testing. What the study actually found was that informing asymptomatic adults about those 56 findings was NOT cost-effective (unless the NGS was very cheap). With universal NGS of asymptomatic babies, of course, every finding will be an “incidental finding”, which will lead to an enormous increase in workload for our genetic counsellors and clinical geneticists. The additional complexity which is added by the fact that huge numbers of genetic variants are of “uncertain pathogenicity” or may be reclassified from being “likely pathogenic” to “likely benign” as more data accumulate, makes the idea of universal sequencing of the whole genome a non-starter.
My recent experience of highly selective NGS has sometimes revealed important diagnoses, and had a benefit for families with a diagnosis. In one case, for example, of an infant with multiple apparently unrelated disorders the diagnosis of MIRAGE syndrome (that I had never heard of) was helpful to stop us searching for other causes. Supportive treatment of each of the problems was organised, and the family were relieved to have an answer. There was, as usual, no specific treatment, but as mentioned that is an extremely rare result of NGS. On the other hand, some families are relieved to hear that the NGS is negative, and that their baby’s problems do not appear to have a genetic cause, that is also a potential benefit.
The message of our article is that the potential and real benefits to some families should not be exaggerated. An appraisal of the value of selective NGS, or of the idea of universal NGS, requires a realistic evaluation of the benefits and also of the adverse impacts on some families. I don’t think NGS will ever be cost effective if you calculate the benefits as QALYs gained, there are so few babies for whom a genetic diagnosis leads to a life prolonging treatment, or a life improving treatment. The very real benefits for some families are much less tangible and impossible to cost. But we must not forget the potential harms also, in order to find ways to minimize them. The advent of truly effective gene therapies (most recently for sickle cell disease) suggests that in the future there may well be a substantial group of conditions which could be treated in presymptomatic babies; that may become another argument for universal NGS screening. Until that happens, and until we figure out how to pay for all the gene therapies that are on their way, I think we should stick to highly selective NGS, and recognize the enormous difficulties in the informed consent process.