Breast Milk is good for you; does it matter how you get it?

The benefits of human, especially mother’s own, breast milk are unambiguous, but is expressed breast milk as good as direct breast-feeding?

A new cohort study from Canada (Klopp A, et al. Modes of Infant Feeding and the Risk of Childhood Asthma: A Prospective Birth Cohort Study. The Journal of pediatrics. 2017;190:192-9 e2) suggests that, in terms of prevention of asthma among term babies, breastmilk is superior to formula, but direct breast-feeding may be superior to giving some expressed breast milk in a bottle. In this prospective study, mothers were questioned about feeding at 3 months of age, and infants were evaluated for definite or probable asthma at 3 years of age. Infants were divided into 4 groups, breast-feeding only, breast-feeding with some breast milk expressed and given via bottle, breast-feeding with some formula supplement, and formula feeding.

Obviously the mothers in the different groups were different, so an attempt was done to correct for the differences in socio-economic status, education, day care attendance of the baby and so on.

They showed a progressively increased prevalence of asthma across the 4 groups :

Is this likely to be true? These questions can always be asked about observational studies, what are the likely confounders, did the authors adequately correct for them and consider others, and is there a plausible explanation for the findings?

The division into breast milk direct only and “some expressed” seems to have been dichotomous, so a mother who expressed nearly all her breast milk, and another who did this once a day or once a week were all in the same group. As far as I can see, even one feed of expressed milk would qualify the baby to be in the second group. There are likely to be other undetected differences between mothers, and perhaps between babies, I can’t see any calculation of when mothers returned to work and why, how much the smoking-mothers smoked (there was a difference in smoking prevalence between groups, but no association with an asthma diagnosis, which seems a little surprising). There are probably other unknown factors also, which is always the case in observational studies.

Is it plausible? There are differences between freshly expressed breast milk and frozen thawed breast milk, for example, after 3 months of freezing lactoferrin has dropped by about 50%, freezing also kills living cells, including immune-modulating cells in breast milk, pretty quickly.  (In contrast, freshly expressed breast milk in glass containers maintained in a domestic refrigerator seems to have little detectable difference to fresh milk). If these are really the potential mechanisms of this possible effect, then the more expressed milk is consumed, and the longer it is frozen should be relevant, the proportion of expressed compared to direct breast milk should be relatively easy to determine, although they may not have noted that in their original data sheets.

It seems inherently unlikely that an occasional feed (perhaps up to once a day) of expressed breast milk in a breastfed baby should have substantial impacts on the health of that baby. Perhaps majority expressed milk or exclusive expressed milk might have an effect which is different to occasional or minority expressed milk.

I think based on this we can say 2 things, encouraging breast-feeding, and making it feasible for new mothers to have several months of leave to breast feed their babies is important (USA, I am talking to you!) There may be an increase in asthma prevalence with mixed breast-feeding and expressed breast milk feeding, this may be due to unknown confounders, but, if causative, it is likely to affect those with the largest proportion of their feeds as expressed milk, however feeding some expressed breast milk which is still preferable to formula feeding.

What about the preterm baby? If a baby is too immature to go directly to the breast, it is clear that the best feeding is mother’s own milk, expressed, and handled appropriately. When possible, and if possible, direct breast-feeding helps, in general, to maintain good milk supply, other potential benefits compared to expressed, stored, breast milk are uncertain.  A recent review of the data regarding breast milk expression and preparation has just been published (Picaud JC, et al. Review concludes that specific recommendations and stringent conditions are needed to harmonise the provision of fresh mother’s milk to their preterm infants. Acta Paediatr. 2018) The review seems quite extensive, and much of the interpretation is appropriate, but I must say I don’t agree with some of the conclusions as shown by the 2 algorithms at the end of the article. They state that any milk expressed at home and given to ELBW or extremely preterm infants  (<1000g or <28 weeks) should be cultured and then pasteurized if there are pathogenic bacteria, in which they include staph aureus, which one study showed was found in almost 100% of expressed breast milk. In addition for the same babies, if the mother is IgG anti-CMV positive, or the status is unknown, then the milk should be pasteurized until the baby reaches 32 weeks.

I am not aware of any evidence of the efficacy of culturing breast milk, and then pasteurizing those with positive cultures, but pasteurizing breast milk has major impacts on its constituents, especially traditional Holder pasteurization. One randomized trial showed a trend toward increased sepsis among preterm babies who received routinely pasteurized compared to raw breast milk. If you use culture independent techniques, about 100% of breast milk is non-sterile (Jost T, et al. Assessment of bacterial diversity in breast milk using culture-dependent and culture-independent approaches. The British journal of nutrition. 2013;110(7):1253-62) and usually contains lactobacilli and bifidobacteria among other things, which will be destroyed by pasteurization. I think if selective culture and pasteurization and going to be used for expressed breast milk in high risk babies, there should be some scientific evidence that this is beneficial, which I cannot find, and the review by Picard does not reference. In fact the only evidence that they refer to that bacterial contamination of expressed milk is a significant hazard are from a publication about contamination of a pasteurizer with Pseudomonas (which is ironic) and a case report of triplets who became colonized with MRSA from mother’s milk. Other data show that milk cultures are not routinely helpful. There are occasional reports of babies becoming septicemic with organisms that can be found in expressed breast milk, but the disadvantages of pasteurization might well outweigh any potential advantage of eliminating pathogens.

Posted in Neonatal Research | Tagged , | Leave a comment

Probiotics might save lives in low-resource countries

After several years of preliminary investigations,  a huge RCT has been published from India (Panigrahi P, et al. A randomized synbiotic trial to prevent sepsis among infants in rural India. Nature. 2017;548:407.) which enrolled babies over 2 kg birth weight between 24 and 96 hours of age to receive a synbiotic mixture, Lactobacillus plantarum with a fructo-oligosaccharide, which they received for 7 days. This followed studies showing that this mixture led to stool colonization for several weeks of life. All the babies were breast-fed, although a few received additional liquids by mouth, including water and honey.

The babies were then followed for up to 60 days to see if they needed evaluation for sepsis, which was diagnosed by WHO criteria. The primary outcome of the trial was the combined outcome of death or sepsis.

They planned to enrol over 8,000 babies, but stopped early after “only” 4,556 babies for efficacy.

The combined outcome of death or sepsis was reduced from 9% in the controls to 5.4% in the synbiotic group. The entire difference being in sepsis, as mortality was low (<0.3%), there was a reduction in gram-negative sepsis, gram-positive sepsis and lower respiratory tract infections, as well as in culture-negative sepsis.

The study was a remarkable achievement, an individually randomized, placebo controlled trial in over 150 villages in India. The study excluded smaller babies, and those thought to be under 35 weeks, as well as 254 suspected to be septic at the time of screening for study entry, and those whose mothers appeared to have perinatal infections. The total number of exclusions came to 2,506. The synbiotics were supplied in capsules with “mixing containers and syringes with needles” initially kept at -20 degrees Celsius then distributed with cold packs. I am not sure exactly how the synbiotics were administered, which I think is an important detail for future wide implementation. I presume the syringe and needle were used to inject a solvent (?sterile water) into the capsules and then aspirate it prior to administering the liquid into the mouth of the baby.

The technical difficulties in distributing and administering this synbiotic preparation as a routine will need to be addressed, but this is an intervention with little or no risk that could improve outcomes for millions of babies around the world.

Posted in Neonatal Research | Leave a comment

Endotracheal intubation, making it safer for babies

Many of our patients need invasive ventilatory support, for which endotracheal intubation is required, but we intubate many fewer babies than in the past. We also very rarely intubate babies for endotracheal suction to remove meconium any longer. Which means that there are vastly fewer opportunities for trainees to learn intubation. I never kept a log while I was training but I am pretty sure that I intubated more babies in my first 2 weeks on a neonatal service than residents now do in their entire training. In addition to the above factors, extended role respiratory therapists and nurse practitioners also need training and experience.

Training juniors and other practitioners to intubate is something I have done many times, usually by showing them the appearances during a laryngoscopy, and talking through the procedure as I performed it, followed by close supervision for a few intubations. It is difficult however, sometimes, to see what they are doing wrong (except when they pick up the laryngoscope with the wrong hand, for example).

There are now 2 RCTs of the use of a video-laryngoscope during the training of intubators in the NICU (one of which was done in my institution, the PI being my colleague Ahmed Moussa), and 2 recent crossover trials of using the video-laryngoscope during training in the simulation lab with mannequins (one of which was by the same Dr Moussa Assaad MA, et al. Learning Neonatal Intubation Using the Videolaryngoscope: A Randomized Trial on Mannequins. Simul Healthc. 2016;11(3):190-3) this is the other one  Parmekar S, et al. Mind the gap: can videolaryngoscopy bridge the competency gap in neonatal endotracheal intubation among pediatric trainees? a randomized controlled study. J Perinatol. 2017.

The results are very consistent, trainees intubate with much more success during initial intubation attempt when using the video-scope, but they take a little longer per attempt; when they then attempt intubation with a conventional laryngoscope they maintain the skills that they learnt.

The two clinical trials also showed similar results, success on initial attempt was much higher with the video, this was despite difference in study design, in the study mentioned already the residents were randomized to using either the video-laryngoscope or a conventional scope, in the other trial they all used the video-scope but were randomized to having the screen covered or not the trainees did not look at the screen in this second study, the supervisor looked at the screen to give them guidance about their technique. The duration of intubation was a little longer with the video compared to the conventional, (Moussa et al) but identical between the video with screen visible and with screen hidden groups; O’Shea et al.

Why do trainees fail to intubate? I think we know the reasons why trainees fail to intubate, but the relative frequency of those causes, and how we can use video-laryngoscopes to reduce and correct them was, I think, unstudied. Until the remarkable Peter Davis (who seems to publish more clinically useful research than anyone else in neonatology, it is hard enough to keep up with the neonatal literature, Peter single-handedly makes it much harder!) and his group reported these data : O’Shea JE, et al. Analysis of unsuccessful intubations in neonates using videolaryngoscopy recordings. Archives of disease in childhood Fetal and neonatal edition. 2017. This is an analysis of video-recordings which were made of both groups in the above mentioned study, even the babies in the screen hidden groups had the videos recorded.

You can see here the categories of failure reasons in the 2 groups, which are similar apart from failure to recognize the vocal cords, presumably a supervisor watching the screen could say “look, there are the cords!” (to which the residents does not respond verbally, while thinking “oh, so that’s what they look like, why aren’t they yellow like in the text-book?”)

The degree of visualization of the glottis was analyzed, and the video-visible group (the intervention group) achieved better visualization, presumably because of the coaching.  (of note there is a header missing over the last column of this table in the published version of the article, I presume the header says ‘C-L grade when inserting ETT in intervention videos (n=14), n%):

I think the video-laryngoscope is clearly an essential tool for teaching neonatal endotracheal intubation, you have to be aware that there are differences between the available devices, the 2 clinical trials highlighted here used different scopes, we use the Storz device, which does not have a 00 blade, and has a somewhat bulkier blade design than a standard Miller blade. Because of this I don’t use it for intubation below about 750 grams. As we don’t teach intubations on babies under 29 weeks that doesn’t cause a huge problem, but I would like to be able to demonstrate the anatomy on smaller babies, and I think even for more senior trainees with experience in intubating bigger babies, the capacity to use the video-scope for coaching in the littlest ones would be invaluable. The Melbourne group used a “Lary-flex” from Acutronic, with a blade which looks more like a traditional Miller blade, and has a 00 available.

As they note in their article, blade design, even among blades which are all named “Miller” differs between manufacturers, a fact of which I have had personal experience, when a hospital changed suppliers, as the alternative was cheaper and had the same appellation, but the blades were quite different and much more of a problem for intubating tiny babies.

Should all intubations be performed with a video-laryngoscope? In the NICU there is little good evidence about use of the video other than for training. A brand new systematic review of intubation complications and how to reduce them (Cabrini L, et al. Tracheal intubation in critically ill patients: a comprehensive systematic review of randomized trials. Critical Care. 2018;22(1):6) showed no clear benefit of video-laryngoscopy for routine intubation, or high risk intubations, and even a higher risk of complications compared to standard laryngoscopy. That is based on post hoc analysis of data from the 2 largest trials (out of the 9 total trials that they found, all in adults).

A review in pediatric patients from a few days ago (Xue F-S, et al. Paediatric video laryngoscopy and airway management: What’s the clinical evidence? Anaesthesia Critical Care & Pain Medicine. 2018) found a large number of articles in children, most of which either excluded newborns, or included very few of them. They were unable to find convincing evidence of the benefit of the video-laryngoscope in clinical practice, and noted the great variations between the 5 models they reviewed (which did not include the Lary-flex).

I think trainees should be taught to intubate using the video-laryngoscope, and, until they are clearly highly competent, all their intubations in the NICU, and perhaps in the delivery room, should be supervised by someone who is highly competent and experienced, and is reviewing the screen showing a video of the process.

Introducing the video for routine intubation of the newborn by individuals who are already experienced and highly competent is not currently supported by any good evidence, although my feeling is that with optimised equipment it may one day become standard of care. This may need further refinement of the equipment, and improvement in blade design, including availability of 00 blades for the tiniest babies.

Endotracheal intubation is associated with frequent adverse events, some serious. Improving the safety of our patients, while ensuring the competence of our trainees as they prepare for independent practice is essential.

Posted in Neonatal Research | Tagged , | 1 Comment

Does tactile stimulation in the delivery room actually do anything?

One of the things that is done in neonatal resuscitation that isn’t part of resuscitating older patients is tactile stimulation. Babies who are apneic and/or floppy often receive stimulation in the form of rubbing the back, patting or flicking the feet, or, in the old days, slapping the butt (sometimes while held upside down by the feet!)

I have never been quite convinced of the efficacy of this, but haven’t thought much about how you would prove if it works or not, or even what “works” would mean. Does tactile stimulation actually start babies breathing sooner? Does it delay effective ventilation? In babies who are bradycardic is there any benefit?

I have seen babies receiving prolonged stimulation with little response, and have even been pushed aside by older nurses while I was trying to ventilate a baby so that they could give a really good rub of the babies back! It is such an ingrained practice that it is accepted uncritically in the initial steps of NRP.

I think it is possible that stimulation has no effect at all, and that the common observation of babies starting breathing after stimulation promotes a confirmation bias, “because they started breathing after being stimulated it must have been because of the stimulation”.

I think it is also possible that stimulation causes reflex respiratory effort, but only in babies that would have started breathing a few seconds later in any case, with no overall benefit.

I think it is also possible that there is enough impact that babies with moderate depression at birth might have a benefit, starting to breathe effectively earlier and even perhaps having an increasing heart rate if mildly bradycardic.

I think it is unlikely that a seriously depressed baby has a benefit, and that, for such a baby, stimulation runs a risk of delaying effective interventions.

How would you prove any of this? It would be difficult to do a prospective RCT, you would have to randomize babies to 2 different NRP type protocols, one with stimulation and one without, you’d need enough babies to include a substantial number who actually need intervention, and then you could look at time to effective ventilation, time to a stable heart rate, or something like that, as the outcome criterion. Could you ethically randomize babies to a no stimulation protocol? Could you get enough people to refrain from stimulation for the study to work?

I think the first thing should be to collect some reliable observational information about the impacts of stimulation. This new study has done just that: Baik-Schneditz N, et al. Tactile stimulation during neonatal transition and its effect on vital parameters in neonates during neonatal transition. Acta Paediatr. 2018 Video recordings and pulse oximeter recordings of babies during transition were analyzed. There were just over 50 term and 50 preterm babies included in the analysis. 18 of the preterms and 25 of the term babies were stimulated at some point. In the preterm group babies were often given respiratory assistance without stimulation, which rarely happened in the term babies, for whom most of the non-stimulated babies did not need any intervention. They weren’t able to measure direct respiratory impacts of stimulation, but they did show in the term babies that there was no change in the saturation or heart rate before and after the stimulation, (comparing the averages for 30 second periods). In the preterm babies heart rate did not change, but saturations increased (which of course might have happened anyway…).

Another study Dekker J, et al. Tactile Stimulation to Stimulate Spontaneous Breathing during Stabilization of Preterm Infants at Birth: A Retrospective Analysis. Frontiers in Pediatrics. 2017;5(61) analyzed practice regarding stimulation among preterm babies. The basic message is that practice was extremely variable. Which to my mind is completely appropriate, as there is really no evidence base for tactile stimulation at term,  and even less (if you can have less than zero without becoming negative) after preterm delivery, then variability in practice should be expected, and should give room for observational studies, and then prospective studies.

Millions of babies are born every year who receive some sort of intervention after birth, failure to adequately adapt to life outside of the womb is a major cause of death and long term disability in the world. Our review of standardized training programs showed that such programs seem to improve survival, and that most survivors have good outcomes.

While awaiting good prospective studies what should we do? I think that, for a term baby with a good heart rate who does not breathe quickly after birth, rubbing the back or flicking their feet is probably harmless and might stimulate an increase in respiratory drive. If the baby is bradycardic or fails to respond within a very short interval (perhaps 20 seconds) then tactile stimulation should quickly be abandoned in favor of positive pressure ventilation.

Posted in Neonatal Research | Tagged | 2 Comments

New Published Letter, a response to the ‘number needed to suffer’.

The new issue of Acta Paediatrica (Februray 2018) includes a letter I wrote in response to a commentary written by a paediatric anaesthetist, Dr Lönnqvist.

If you receive an email with a description of the contents of each issue, as I do, you may have seen this :

A number of papers explore the outcomes of extremely preterm infants. Gillone et al state that the one-year survival rate for babies born at less than 501 grams in the North of England was only 22% in 1998-2012. Lynoe et al ask what the indications should be for providing extremely preterm infants with neonatal intensive care and Lönnqvist proposes that disability-free survival and the number needed to suffer should be used as outcome measures for such care. He claims that it is misleading to just focus on saving lives, without paying attention to the risk of severe disabilities, poor quality of life and the suffering of families. Helgesson agrees with Lönnqvist, while Barrington strongly disagrees.

That brief description mischaracterizes the points that I made. Dr Lönnqvist wrote his ‘A Different View’ claiming that disability-free survival was a new concept that should be used as the primary focus on decision making for extremely preterm infants.

That, of course, is ridiculous, as I noted in my letter, disability-free survival has been an unfortunate focus of neonatal outcome studies for decades; I say unfortunate because calculation of such an index conflates death and ‘disability’. The point I made is that both death and disability are important, but they should be considered separately, not lumped together as if they had equivalent impact, or were treated and valued the same by families. Of course, as you will know if you are a frequent reader of this blog, so-called ‘disability’, as included in most long term outcome studies, usually means low scores on developmental screening tests, and not the presence of a disabling condition.

To emphasize a point I have made many times, “NDI”, which stands for Neuro-Developmental Impairment, is an abusive misnomer. Most babies who are thus labelled are listed as being impaired because of lower scores on developmental screening tests, like the Bayley Scales of Infant Development. But a Bayley version 2 MDI score under 70 (or a Bayley 3 language or cognitive composite under 85, or indeed a score on any standardized developmental screening test below an arbitrary cutoff) is not an impairment. An impairment is “a loss or abnormality of psychological, physiological or anatomical structure or function”; infants with a developmental test score below a particular threshold do not, by this definition, have an impairment. If their developmental difficulties affect their function, then they may have an impairment, but most babies with lower screening scores have no functional ‘abnormality’, and are not impaired.

Dr Lonnqvist’s belief that disability-free survival was a new concept demonstrated to me how little he knew about the field. But more disturbing to me was Dr Lönnqvist‘s attempt to create a new metric to determine the impact of survival among high-risk newborns. He called this the ‘number needed to suffer’, which is calculated as I noted in my reply, part of which is reproduced below:

Dr Lönnqvist’s calculation of the ‘number needed to suffer’ requires that he conflates impairment with suffering. His idea that a day of living with an impairment is equivalent to a day of suffering is completely unacceptable. His calculations of ‘number needed to suffer’ require that infants who die before they leave the NICU have the sum of their ‘days of suffering’ calculated. This is then added to the number of days of life of children at follow-up who have impairments to calculate the denominator of suffering. According to his calculations, the numerator is the number of babies who survive without impairment. Again, according to this nonsensical metric, as the children get older the ‘number needed to suffer’ increases each day, because, according to this calculation, having an impairment means daily suffering. At 3.5 years, he calculates a number needed to suffer of 1/1369, at 10 years, if we counted minutes rather than days, the NNS would be in the billions!

As I point out in my letter, an issue to which Dr Lönnqvist does not respond in his answer (also published on-line simultaneously), if we follow his reasoning, any surgery for a child who is already blind or has cerebral palsy would be unconscionable, their ‘disability free survival’ would be zero and their ‘number needed to suffer’ would be infinite.

Despite the prejudices of Dr Lönnqvist and others of like mind, most extremely preterm babies who survive do so without serious impairment, even those who really do have serious impairments have a good quality of life, and there is little impact of gestational age at birth on the frequency of impairment.

In his reply to my letter, Dr Lönnqvist suggests that babies in the south of Sweden born at 24 weeks gestation have better outcomes than babies in the North, and that this is because of the vacuuming up of resources by the 22 weekers, who are much more likely to receive active care in the North than in the South.

This is, of course, nonsense. Admitting one of the 3 or 4 babies of 22 or 23 weeks gestation each year in an NICU has no perceptible impact on resource utilisation overall for an NICU (there were about 50 deliveries at 22 weeks over a 3 year period, they were admitted to one of 7 NICUs). There is no reasonable way you could calculate the impact of such an admission. The data presented by Dr Lönnqvist are neither peer-reviewed nor are they adjusted for baseline risks, he presents unverifiable data (which incidentally appeared on the front cover of Acta Pediatrica a few years ago) from what he says are Swedish government sources (in the legend to the figure he states that these are from “post-publication data processing” of the EXPRESS cohort) we have no idea if those data include delivery room deaths, how they were collected etc. etc. In fact the numbers in that figure are not the same as any numbers in the original cohort, neither the numbers of fetuses alive at admission of the mother, nor the number of live births.

In the original publication prior to the “post-publication data processing” you can see from this figure that the births at 22, 23 and 24 weeks were considered together. You can also see that the centers with the lowest odds of death at 25 to 26 weeks were the centers that also had the lowest odds of death at 22 to 24 weeks, that is Uppsala, Lund, Orebro and Umea.

None of which suggests that more mature babies are less likely to receive optimal care if the most immature babies also receive it, quite the opposite. Indeed multiple other data sources also strongly suggest the opposite, if you are active in the care of the most immature babies, you do a better job with the slightly less immature ones.

In his reply to my letter Dr Lonnqvist states that data describing the long term outcomes of infants who had surgical NEC are limited, which they are not. There is a substantial literature describing the outcomes of infants with NEC, including the subgroup with surgical NEC; the adverse impacts of this terrible disease are well documented, there are over 40, and maybe as many as 60, articles which address these issues.

One of the best recent papers, from last year in the Journal of Pediatric Surgery, shows that if you define serious adverse outcome to include a Bayley version 2 score under 70 at 18 months of age (which I would not, that is not something that is of importance to most families), then the majority (62%) of extremely low birth weight infants (<1000g birth weight) with surgical NEC who survive are free of serious adverse neurological impairment or developmental delay. There are few data, to my knowledge, of even later outcomes of such babies, it would be interesting to know how many babies with surgical NEC have serious functional disability at 5 years of age, for example. That would be much more relevant to most families, I believe. There are data from Calgary about outcomes at 36 months of babies under 1250 g who had NEC, but no analysis of those with surgical as opposed to medical NEC (76% of NEC survivors had no developmental delay or neurologic problem at 36 months in this study).

Surgical NEC is indeed a bad disease, with substantial mortality and an increase in neurologic problems and developmental delay among survivors. It is certainly something we should try to avoid, and to treat as appropriately as possible. But most survivors, even the extremely low birth weight, still have good neurological and developmental outcomes. Making blanket decisions to operate or not should not be based on simplistic reductions of risk to gestational age, nor by conflating the risk of death with the risks of developmental delay and other adverse outcomes. We should individualize our decision-making discussions; which means that, for a 23 week gestation infant without other additional risk factors, a decision to perform surgery might be perfectly in line with the parents’ values, and present a reasonable chance of survival and of a good long term outcome: for a 25 week gestation infant who has already had several other risk factors when he perforates at 4 weeks of age, a decision to institute comfort care might be completely reasonable, and consistent with the parents’ values. Decision-making should definitely not be based on nonsensical calculations of “number needed to suffer” which explicitly equate living with a developmental delay with suffering.

Posted in Neonatal Research | Tagged , , | Leave a comment

Curing genetic diseases

One of the most difficult things that we have to deal with, as neonatologists and pediatricians, is to announce the diagnosis of a lethal, or a lifelong life-changing, genetic diagnosis. Spinal Muscular Atrophy (Werdnig-Hoffman disease), and Haemophilia A are 2 such diseases. These are examples of the kind of disease that would be great if we could correct the abnormal gene, a dream that has been around since we discovered the genetic basis of those disorders.

Well now it appears that this might soon be truly possible. After several mis-steps, and unsuccessful attempts at gene therapy in the past, 2 recent issues of the New England Journal of Medicine have announced successful apparent partial genetic correction. Mendell JR, et al. Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy. New England Journal of Medicine. 2017;377(18):1713-22. In this study there were 2 dose schedules, the low dose schedule was tolerated, but not very effective, the high dose schedule led to achievement of motor milestones that are not normally achieved by infants with this disorder. By 18 months of age most babies with type 1 SMA are normally either dead or permanently ventilated, in this group none of them were. It seems like the treatment was still effective out to 2 years after the single infusion.

The other remarkable advance is gene therapy for hemophilia A. Nine severely affected men had a single intravenous infusion of gene therapy, and 6 of the 7 who had the high dose had complete normalization of their factor 8 levels, the 7th had increased levels up to mild hemophilia concentrations. Up to a year after the treatment factor 8 levels remained good, and there was a marked clinical improvement.

Further follow-up will be required to be sure that these interventions are safe, both used adenovirus vectors to deliver the genetic therapy, but in both studies there were only transient mild hepatic effects of the viral vector.

One day delivering the distressing diagnosis of SMA type 1, or hemophilia A will become an opportunity for cure rather than the death-sentence, or life-sentence, that they now are. Let’s hope that the availability and price will be such that all eligible babies will be able to receive therapy.

Posted in Neonatal Research | Leave a comment

Inhaled Steroids to Prevent BPD? Think again… again!

The NEUROSIS trial that I discussed in my previous post has, among other published trials, most in common with the trial by Nakamura published in 2016. Nakamura T, et al. Early inhaled steroid use in extremely low birthweight infants: a randomised controlled trial. Archives of disease in childhood Fetal and neonatal edition. 2016. That was a trial of very early (<24 hours) inhaled fluticasone given every 12 hours for up to 6 weeks to ELBW infants. Unlike many of the other trials in recent systematic reviews, this was a recent trial with a decent sample size (n=211) and with truly prophylactic administration. The main differences between Nakamura et al and NEUROSIS were that Nakamura only enrolled intubated babies, and the fluticasone (not budesonide as in NEUROSIS) was stopped once the babies were extubated.

Most of the analyses in the Cochrane review that I discussed do not include data from this moderately sized, recent, high quality trial, because the authors chose to define lung injury by the need for oxygen at discharge, rather than at 36 weeks. To me that is a great strength of this study!

The authors of this study found no difference in the combined outcome of death or needing oxygen at discharge (14% with fluticasone, 22% with placebo), but they showed very similar trends to NEUROSIS, with an increase in mortality of 39% with inhaled steroids. That result could, of course, have been due to chance, but it is entirely consistent with the results from NEUROSIS.

As far as I am aware these are the only 2 trials of reasonable size, of prophylactic inhaled steroid use, from the last decade of neonatology, which have reported death before discharge among very immature newborns. If we put their data together, this is what we get: (using Revman 5, random effects model)

A very worrying consistent increase in pre-discharge mortality between the 2 trials, with a lower confidence limit of 1.02.

The numbers needing home oxygen can be calculated from Nakamura (just by subtracting death before discharge from the combined outcome) and that gives the following risk difference, again using the random effects model:

A possible 5% reduction in the need for home oxygen, among survivors to discharge, which may be due to random variation, the 95% confidence intervals include no effect (RD=0).

The Nakamura study reported the long-term neurological and developmental outcomes of their study infants also, and showed no difference in the combined outcome of ‘death or NDI’, numerically these were all slightly higher in the fluticasone group, so presumably identical between groups if you were just to look at the survivors.

The only other trial I can find of inhaled steroids initiated on day one is the pilot trial of Zimmerman et al, enrolling 39 infants in total of < 1301 g birth weight. For some reason this trial is not mentioned in the recent Cochrane review, either as included or excluded, so I guess their search missed it. It was published in October 2000, and is reported as being randomized. In the placebo group there were 2 deaths, and 2 babies transferred out for surgery, for whom no other outcome data are given, in the beclomethasone group there were 3 deaths.  As it is uncertain whether the 2 surgical babies survived, and not clear whether babies needed oxygen at discharge, I have not added their data to the Forest plots above.

I think the 2 other studies are similar enough, in design and in results, to give us some confidence to say that very early inhaled steroids given to extremely immature newborn infants on the first day of life have no clear pulmonary benefit of importance, and may well increase mortality, without an impact of neurological or developmental outcomes among survivors.


Posted in Neonatal Research | Tagged , , , , | Leave a comment