AllThingsNeonatal

Choosing to provide postnatal systemic steroids to preterm infants for treatment of evolving BPD has given many to pause before choosing to administer them. Ever since K Barrington published his systematic review The adverse neuro-developmental effects of postnatal steroids in the preterm infant: a systematic review of RCTs. and found a 186% increase in risk of CP among those who received these treatments, efforts have been made to minimize risk when these are given. Such efforts have included shortening the exposure from the length 42 day courses and also decreasing the cumulative dose of dexamethasone. Fortunately these efforts have led to findings that these two approaches have not been associated with adverse neurodevelopmental outcomes. Having said that, I doubt there is a Neonatologist that still doesn’t at least think about long term outcome when deciding to give dexamethasone. The systemic application certainly will have effects on the lung but the circulating steroid in the brain is what occupies our thoughts. What About Applying it Directly to the Lung If you wanted to prevent BPD the way to do it would be to minimize the time infants are exposed to positive pressure ventilation. Rather than giving steroids after a week or two maybe it would be best to give them early. Recent evidence supports this for systemic steroids and has been written about recently. Hydrocortisone after birth may benefit the smallest preemies the most! This still involves providing steroid systemically. Over the years, inhaled steroids have been tried as have intratracheal instillation of steroid with and without surfactant as a vehicle for distribution to the lung. This month colleagues of mine anchored by Dr. G. t’Jong (a founding member of the “Tall Men of Pediatrics #TMOP) published a systematic review and meta-analysis of all such RCTs in their paper Efficacy and safety of pulmonary application of corticosteroids in preterm infants with respiratory distress syndrome: a systematic review and metaanalysis. The results of the study suggest that there may well be a role for this approach. All of the included studies used a prophylactic approach of giving between the first 4 hours and the 14th day of postnatal age doses of pulmonary steroids with the goal of preventing death or BPD. The GA of enrolled infants ranged from 26 to 34 weeks, and the birth weight ranged from 801 to 1591 g. Out of 870 possible articles only 12 made the cut and compromised the data for the analysis. Routes of steroid were by inhalation, liquid instillation though the endotracheal tube or by mixing in surfactant and administering through the ETT. What Did They Find? Using 36 weeks corrected age as a time point for BPD or death, the forrest plot demonstrated the following. A reduction in risk of BPD or death of 15% with a range of 24% to only a 4% reduction. Looking at the method of administration though is where I find things get particularly interesting. What this demonstrates is that how you give the steroids matters. If you use the inhalational or intratracheal instillation (without a vehicle to distribute the steroids) there is no benefit in reduction of BPD or death. If however you use a vehicle (in both Yeh studies it was surfactant) you find a significant reduction in this outcome. In fact if you just look at the studies by Yeh the reduction is 36% (CI 34 – 47%). In terms of reduction of risk these are big numbers. So big one needs to question if the numbers are real in the long run. Why might this work though? In the larger study by Yeh, budesonide was mixed with surfactant and delivered to intubated infants every 8 hours until FiO2 was less than 30%, they were extubated or a maximum of 6 doses were reached. We know that surfactant spreads throughout the lung very nicely so it stands to reason that the budesonide could have been delivered evenly throughout the lung. Compare this with inhalational steroid that most likely winds up on the plastic tubing or proximal airway. The anti-inflammatory nature of steroids should decrease damage in the distal airways offsetting the effects of positive pressure ventilation. Future Directions I am excited by these findings (if you couldn’t tell). What we don’t know though is whether the belief that the steroid stays in the lung is true. Are we just making ourselves feel better by believing that the steroid won’t be absorbed and move systemically. This needs to be tested and I believe results of such testing will be along in the near future. Secondly, we need a bigger study or at least another to add to the body of research being done. Such a study will also need long term follow-up to determine if this strategy does at least have equal neurodevelopmental outcomes to the children who don’t receive steroid. The meta-analysis above does show in a handful of studies that long term outcome was no different but given the history of steroids here I suspect we will need exceptionally strong evidence to see this practice go mainstream. What I do believe is whether you choose to use steroids prophylactically using hydrocortisone or using intratracheal surfactant delivered budesonide, we will see one or both of these strategies eventually utilized in NICUs before long.

The medical term for this is placentophagy and it is a real thing. If you follow the lay press you may have seen that originally this was promoted by Kourtney Kardashian who did this herself and then by Kim who planned on doing the same after delivery. See Did Kourtney Kardashian Eat Her Placenta? This is not completely without basis as many readers will be thinking already that they have heard about the health benefits of doing the same. Reports of improved mood and reductions in the baby blues following ingestion of placenta as well as improvements in breast milk production have led to this growing practice. The evidence for this up until recently though was quite old and fraught with poorly design of such studies. The bigger driver however has been word of mouth as many women having heard about the promises of better mood at the very least have thought “why not? Can’t hurt.” What I will do in this post is run through a little background and a few recent studies that have shed some light on how likely this is to actually work. Where did the idea come from? Animals eat their placentas after delivery. It turns out that unprocessed placenta is quite high in the hormone prolactin which is instrumental for breastfeeding. Given the large amount of this hormone as well as the number of other hormones present in such tissue it was thought that the same benefits would be found in humans. Eating unprocessed human tissue whether it is put in a capsule or not is unwise as unwanted bacteria can be consumed. In fact, a case of GBS sepsis has been linked to such a practice in which the source of the GBS was thought to be due to contaminated unprocessed maternal placenta that had been ingested. Buser GL, Mat´o S, Zhang AY, Metcalf BJ, Beall B, Thomas AR. Notes from the field: Late-onset infant group B streptococcus infection associated with maternal consumption of capsules containing dehydrated placenta. What happens when you process placenta by steaming and drying? This would be the most common way of getting it into capsules. This process which renders it safe to consume may have significant effects on reducing hormonal levels.This was found in a recent study that measured oxytocin and human placental lactogen (both involved positively in lactation) and found reductions in both of 99.5% and 89.2%, respectively compared versus raw placenta. I would assume that other hormones would be similarly affected so how much prolactin might actually wind up in these capsules after all? Clinical Randomized Double Blind Controlled Trial Twenty seven women from Las Vegas were recruited into a pilot trial (12 beef placebo vs 15 steamed and dried placenta) with the authors examining three different outcomes across three studies. The first study Effects of placentophagy on maternal salivary hormones: A pilot trial, part 1 looked at a large number of salivary hormones at four time points. Plasma samples were taken as well to determine the volume of distribution of the same. First samples were at week 36 of gestation then within 4 days (96 h) of birth followed by days 5–7 (120–168 h) postpartum and finally Days 21–27 (504–648 h) postpartum. All consumption of capsules was done in the home as was collection of samples. As per the authors in terms of consumption it was as follows “two 550 mg capsules three times daily for the first 4 days; two 550 mg capsules twice daily on days 5 through 12, and then to decrease the dose to two 550 mg capsules once daily for the remainder of the study (days 13 through approximately day 20 of supplementation). Outcomes No difference was found between salivary concentrations of hormones at any time point other than that with time they declined following birth. Curiously the volume of distribution of the hormones in serum was slightly higher in the placenta capsule groups but not enough to influence the salivary concentrations. It was felt moreover that the amount of incremental hormone level found in the serum was unlikely to lead to any clinical response. The second study was on mood Placentophagy’s effects on mood, bonding, and fatigue: A pilot trial, part 2. Overall there were no differences for the groups but they did find “some evidence of a decrease in depressive symptoms within the placenta group but not the placebo group, and reduced fatigue in placenta group participants at the end of the study compared to the placebo group.” The last paper published from the same cohort is Ingestion of Steamed and Dehydrated Placenta Capsules Does Not Affect Postpartum Plasma Prolactin Levels or Neonatal Weight Gain: Results from a Randomized, Double-Bind, Placebo-Controlled Pilot Study. This study specifically addressed the issue of prolactin levels and found no difference between the groups. Neonatal weight gain was used as a proxy for breastmilk production as it was thought that if there was an effect on breastmilk you would see better weight gain. About 80% in both groups exclusively breastfed so the influence of formula one can’t take out of the equation. In the end weight gain was no different between groups although a trend to better weight gain was seen in the placebo group. To eat or not to eat that is the question? What is clear to me is that the answer to this question remains unclear! What is clear is that I don’t think it is wise to consume raw placenta due to the risks of bacterial contamination. Secondly, the levels of hormones left in the placental preparation and the most common preparation of steaming and drying leave hormone levels that are unlikely to influence much at all from a biochemical standpoint. It also seems that breastmilk production and neonatal weight gain aren’t influenced much by consumption of these pills. The issue though in all of this is that while the previous research was of low quality, the current research while of better quality is at a low volume. These were pilot trials and not powered to find a difference likely. The finding in the subgroup of some effect on mood at the end of the study does leave some hope to those that believe in the power of the placenta to help. Would a larger study find benefit to this practice? My suspicion from a biochemical standpoint is not but that one may feel a benefit from a placebo response. Should you go out and have your placenta prepared for consumption? If you have Kardashian like wealth then go for it if you think it will help. If you don’t then I would suggest waiting for something more definitive before spending your money on placentophagy.

This post is very exciting to me. All of us in the field of Neonatology are used to staring at patient monitors. With each version of whatever product we are using there seems to be a new feature that is added to soothe our appetites for more data. The real estate on the screen is becoming more and more precious as various devices such as ventilators, NIRS and other machines become capable of displaying their information in a centralized place. The issue though is that there is only so much space available to display all of this information but underneath the hood so to speak is so much more! Come Along For The Ride One of our Neonatologists Dr. Yasser Elsayed has been very aware of these features embedded in the patient monitor. Through teaching on rounds, some of our staff have become aware of these features but delivering this content to the masses has been an issue. That is where this post and it’s linked content come into play. I have created a new Youtube playlist where all of this great content can be found. Each video is very watchable with most being 5-7 minutes long with the longest being 14:16. Each video starts with a demonstration on the patient monitor of the lesson being taught and how to access the data using the patient monitor (in this case a Phillips but I have no doubt many other monitors have the same tech – just ask your rep how to get it) followed by a brief voice-over powerpoint to deliver the essential concepts. However you wish to digest the information is up to you but as they are short we hope that you will be able to find the content you need quickly and apply the knowledge to patient care. How can you use the information? The next time a patient is giving you cause to worry try looking into some of the deeper trends that the monitor is hiding from plain sight. Is there a trend towards becoming hypotensive for the patient that can be revealed in their blood pressure histogram? Maybe the issue lies with the way the patient is being ventilated and examining trends in the pleth waveforms may reveal where the underlying problem lies. The Topics (click the links to go to Youtube) Complete List of Videos Part 1 – Using Histograms Part 2 – How to interpret blood pressure histograms Part 3 – Using vital signs as trends Part 4 – Impact of ventilation on pleth waveforms Part 5 – How to interpret arterial pressure waveforms Part 6 – Near Infrared Spectroscopy

A recent post on the intranasal application of breast milk Can intranasal application of breastmilk cure severe IVH? garnered a lot of attention and importantly comments. Many of the comments were related to other uses for breast milk (almost all of which I had no idea about). A quick search by google uncovered MANY articles from the lay press on such uses from treating ear infections to diaper dermatitis. One such article 6 Surprising Natural Uses For Breast Milk certainly makes this liquid gold sound like just that! This got me thinking as I read through the claims as to how much of this is backed by science and how much is based on experience of mothers who have tried using breast milk for a variety of unconventional treatments. I was intrigued by the claim about acne as with several family members nearing that wonderful period of the teenage years I wondered might there have been a treatment right under my nose all this time? Before going on I will tell you what this post is not. This is not going to be about telling everyone that this is a terrible idea. What this is about is breaking down the science that is behind the articles that have surfaced on the internet about its use. I thought it was interesting and I hope you do too! The Year Was 2009 The story begins here (or at least this is the point that I found some evidence). A group of nanoengineering researchers published a paper entitled The antimicrobial activity of liposomal lauric acids against Propionibacterium acnes. The authors examined the antibacterial effect of three fatty acids one of which was lauric acid (which is found in coconut oil but also in breast milk) against Propionibacterium acnes (P. acnes) the bacterium responsible for acne in those teen years. The results in terms of dose response to lauric acid was quite significant. This is where the link in the story begins. Lauric acid kills P. Acne and it is found in high concentrations in breast milk so might topical application of breast milk treat acne? From what I can see this concept didn’t take off right away but a few years later it would. Next we move on to 2013 This same group published In vivo treatment of Propionibacterium acnes infection with liposomal lauric acids. in 2013. This time around they used a mouse model and demonstrated activity against P. Acnes using a liposomal gel delivery system to get the Lauric acid onto the skin of the mouse. Interestingly, the gel did not cause any irritation of the mouse skin but using the traditional benzoyl peroxide and salicylic acid caused severe irritation. From this it appears that the news story broke about using breast milk to treat acne as I note several lay press news stories about the same after 2013. Let’s be clear though about what the state of knowledge is at this point. Lauric acid kills P. Acne without irritating skin in a mouse model. As with many early discoveries people can get very excited and apply the same to humans after extrapolation. What Happened Since Then? Well, in late 2018 this study was released Design, preparation, and evaluation of liposomal gel formulations for treatment of acne: in vitro and in vivo studies. This is another animal study but this time in the rat which demonstrated application of the gel led to “∼2 fold reduction in comedones count and cytokines (TNF-α and IL-1β) on co-application with curcumin and lauric acid liposomal gel compared to placebo treated group.” Essentially, comedones were reduced and markers of inflammation. So not only do we see an antimicrobial effect, once the bacteria are erradicated, there is a clinical reduction in acne lesions! Where do we go from here? This story is still evolving. Based on the animal research thus far here is what I believe. 1. Lauric acid a fatty acid found in breast milk can kill P. Acne. 2. Lauric acid provided in a gel form and topically applied to rodents with acne can achieve clinical benefits. 3. Whereas current standard treatments of benzoyl peroxide and salicylic acid cause inflammation of the skin with a red complexion, lauric acid does not seem to have that effect. These are pretty incredible findings and I have no doubt, pharmaceutical companies will be bringing forth treatments with lauric acid face creams (they already exist) with a target for acne soon enough. The question though is whether families should go the “natural route” and apply expressed breast milk to their teenagers face. Aside from the issue of whether or not your teenager would allow that if they knew what it was the other question is what might grow on the skin where breast milk is left. I am not aware of any further studies looking at other bacteria (since P. Acnes certainly isn’t welcome around breast milk) but that is one potential concern. In the end though I think the research is still a little premature. We don’t have human trials at this point although I suspect they are coming. Can I say this is a terrible idea if you are currently using breast milk in such a fashion? I suppose I can’t as there is some data presented above that would give some credibility to the strategy. I am curious for those who read this post what your experience has been if you have used breast milk for acne or for other skin conditions. Does it really work?!?

Hypoglycemia has been a frequent topic of posts over the last few years. Specifically, the use of dextrose gels to avoid admission for hypoglycemia and evidence that such a strategy in not associated with adverse outcomes in childhood. What we know is that dextrose gels work and for those centres that have embraced this strategy a reduction in IV treatment with dextrose has been noted as well. Dextrose gels however in the trials were designed to test the hypothesis that use of 0.5 mL/kg of 40% dextrose gel would be an effective strategy for managing hypoglycemia. In the Sugar Babies trial the dextrose gel was custom made and in so doing an element of quality control was made possible. In Canada we have had access to a couple products for use in the newborn; instaglucose and dex4. Both products are listed as being a 40% dextrose gel but since they are not made in house so to speak it leaves open the question of how consistent the product is. Researchers in British Columbia sought to examine how consistent the gels were in overall content and throughout the gel in the tube. The paper by A. Solimano et al is entitled Dextrose gels for neonatal transitional hypoglycemia: What are we giving our babies? As an aside, the lead author Alfonso was just announced as the 2019 recipient of the Canadian Pediatric Society Distinguished Neonatologist award so I couldn’t see a better time to provide some thoughts on this paper! What did they find? The study examined three tubes each of instaglucose and dex4. For each tube the researchers sampled dextrose gel from the top, middle and bottom and then the dextrose content per gram of gel determined as well as gel density. Glucose concentrations were analyzed high-pressure liquid chromatography tandem mass spectrometry (HPLC-MS/MS) and gas chromatography mass spectrometry (GCMS) were used to determine glucose concentrations and identify other carbohydrates, respectively. In terms of consistency the gels were found to be quite variable with dextrose content that for instaglucose could be as much as 81% and 43% different for dex4. Differences also existed between the different sections of the tubes so depending on the whether it was a fresh tube you were using or not the amount of dextrose could vary. The authors also discovered that while dex4 contained almost exclusively dextrose, instaglucose contained other carbohydrates not listed on the manufacturer’s ingredient list. What does it all mean? The differences are interesting for sure. If the glucose gels are not consistent though should we stop using them? I think the answer to that at least for me is no. Although the data is unpublished, our own centres experience has been that admissions for hypoglycemia have indeed fallen since the introduction of dextrose gel usage (we use instaglucose). What I can only surmise is that in some cases patients may be getting 40% but perhaps in others they are getting as little as 20% or as much as 60% (I don’t know exactly what the range would be but just using this as an example). In some cases of “gel failure” perhaps it is for some babies, receipt of low dextrose containing gel that is at fault or it may be they just have high glucose requirements that gel is not enough to overcome. Other infants who respond quickly to glucose gel may be getting a large dose of dextrose in comparison. Overall though, it still seems to be effective. What I take from this study is certainly that there is variation in the commercially prepared product. Producing the gel in the hospital pharmacy might allow for better quality control and would seem to be something worth pursuing.

It isn’t often in Neonatology these days that something truly innovative comes along. While the study I will be discussing is certainly small I think it represents the start of something bigger that we will see evolve over the coming years. There is no question that the benefits of mother’s own milk are extensive and include such positive outcomes as improved cognition in preterm infants and reductions in NEC. The benefits come from the immunological properties as well as the microbiome modifying nature of this source of nutrition and have been discussed many times over. Mother’s own milk contains a couple of very special things that form the basis of the reason for the study to be presented. What are neurotrophins and stem cells? Before discussing the study it is important to understand what these two classes of molecules and cells are capable of. Neurotrophins are molecules that have the capability of promoting growth and survival of neural cells. Included in this class are EGF, brain-derived neurotrophic factor, glial derived neurotrophic factor, nerve growth factor, insulin-like growth factor-1, and hepatic growth factor. It turns out that not only are these found in high concentrations in breast milk but that a woman who produces breast milk at early gestational ages has higher amounts of these substances in her milk. Pretty convenient that substances promoting development of the brain and survival of brain cells increase the earlier you deliver! Stem cells are pluripotent cells meaning that they can develop into pretty much any cell type that they need to in the body. This would come in handy for example if you needed some new cells in the brain after a neurological insult. These are also present in mother’s milk and in fact can represent as much as 30% of the population of cells in breast milk. The Nasal Cavity and the Brain Clearly, the distance from the nasal cavity to the brain is relatively short. Without going into exhaustive detail it has been demonstrated in animal models that provision of medications intranasally can reach the brain without traversing the blood stream. This affords the opportunity to provide substances to the neonate through the nasal cavity in the hopes that it will reach the brain and achieve the desired effect. When you think about it, newborns when feeding have contact between the whole nasopharyngeal cavity and milk (as evidenced by milk occasionally dripping out of the nose when feeding) so using an NG as we do in the NICU bypasses this part of the body. Is that a good thing? Intranasal application of breast milk Researchers in Germany led by Dr. Kribs published an early experience with this strategy in their article Intranasal breast milk for premature infants with severe intraventricular hemorrhage—an observation. In this paper the strategy;follows; 2 × 0.1 ml of his or her mother’s milk 3 to 8 times a day (0.6 to 1.6 ml total per day). The breast milk was freshly expressed, which means the milk was used within 2 h after expression. The daily application started within the first 5 days of life and was continued for at least 28 days to a maximum of 105 days. The outcome of interest was whether the severe IVH would improve over time compared to a cohort of infants with severe IVH who did not receive this treatment. Importantly this was not a randomized trial and the numbers are small. A total of 31 infants were included with 16 receiving this treatment and 15 not. The two groups were compared with the results as follows. The results don’t reach statistical significance but there is a trend at the bottom of the table above to having less progressive ventricular dilatation and surgery for the same. Again this is a very small study so take the results with a grain of salt! Is this practice changing? Not yet but it does beg the question of what a properly designed RCT might look like. The authors predict what it might look like with a sham nasal application versus fresh mother’s milk. I do wonder though if it may become a study that would be hard to recruit into as when families are approached and the potential benefit explained it may be hard to get them to say anything other than “Just give my baby the breast milk!” Such is the challenge with RCTs so it may be that a larger retrospective study will have to do first. Regardless, be on the lookout for this research as I suspect we may see more studies such as this coming and soon! * Featured image from the open access paper. (There couldn’t be a better picture of this out there!)

InSurE (Intubate, Surfactant, Extubate) has been the standard approach for some time when it comes to treating RDS. Less Invasive Surfactant Administration (LISA) or Minimally Invasive Surfactant Administration (MIST) have been growing in popularity as an alternative technique. More than just popular, the techniques have been shown to reduce some important short term and possibly long term outcomes when used instead of the InSurE approach. Aldana-Aquirre et al published the most recent systematic review on the topic in Less invasive surfactant administration versus intubation for surfactant delivery in preterm infants with respiratory distress syndrome: a systematic review and meta-analysis. They demonstrated that when looking at 6 RCTs with 895 infants, the overall results indicate that use of LISA instead of InSurE leads to a lower rate of death or bronchopulmonary dysplasia (BPD) at 36 weeks (risk ratio (RR)=0.75 (95% CI 0.59 to 0.94), p=0.01) and the need for mechanical ventilation within 72 hours of birth (RR=0.71 (0.53 to 0.96), p=0.02) or anytime during the patient stay in the NICU (RR=0.66 (0.47 to 0.93), p=0.02). This study has been out for two years this month and yet here we are at least in my centre still performing InSurE. Why is that? One reason likely has something to do with the expression "you can't teach an old dog new tricks". We know how to do InSurE and we are pretty good at it. Performing the LISA technique is not just about putting a catheter in the airway and instilling surfactant. There are several steps that need to be done in order to ensure that the surfactant goes where it is supposed to so there is training required but such training is available in videos posted on the internet or I am sure available from centres willing to share their methods. Still it takes someone declaring we need to change before anything will happen. The second reason for this insistence on the status quo has been the availability of only a large volume surfactant in Canada at 5 ml/kg while in European centres the volume administered was half that. Now a low volume surfactant is available in Canada but some centres have been slow to make a switch due to comfort with the current product. The drawback to the current product is the concern that you can't use it for LISA techniques since the centres practicing this technique use the low volume form. Can High Volume Be Used For Lisa? Researchers in London, Ontario performed a retrospective cohort study of 43 infants in their institution who underwent the MIST approach for surfactant administration in their study High-volume surfactant administration using a minimally invasive technique: Experience from a Canadian Neonatal Intensive Care Unit. In 2016, London instituted a change in practice to provide MIST for infants born at ≥28 weeks and/or with a birth weight ≥ 1,000 g with respiratory distress syndrome. Surfactant was provided over 1-3 minutes via a MAC catheter guided through the vocal cords with Magill forceps. What I like about this study is the reproducibility of it as the authors describe very nicely how the steps were done. What I also appreciate is the provision of sucrose and atropine prior to the procedure. Not a rapid sequence induction but it does do something to address the risk of bradycardia and discomfort with cannulation of the trachea. The results I think speak for themselves that this is indeed possible as 41/43 neonates underwent the procedure with successful instillation of surfactant confirmed by absence of recovered surfactant in aspirated stomach contents. All of these infants qualified for BLES based on an oxygen requirement on non-invasive support of 40% or more. These patients are similar to our own in Winnipeg in terms of qualifying criteria for surfactant but perhaps a little higher tolerance of FiO2 before intubating. Additional evidence that surfactant was indeed received was the reduction to room air in 85% of patients within 24 hours and also the need for a second dose of surfactant in only 10%. Aside from oxygen desaturation in about 50% during BLES administration the adverse effects were fairly limited and similar to what one would see with InSurE. What now? BLES can be administed via MIST despite concerns about the higher volume of surfactant. What many centres need to address I suspect is that while we think we are practicing InSurE, in many cases we are not. The goal of that procedure is to provide the surfactant over a few seconds and then get the ETT out right away. How often does that happen though in reality? Have you ever found yourself leaving the ETT in till the baby gets to NICU and extubating there? Seems safer right? What if in the elevator or hallway on the way to NICU the baby deteriorates and needs intubation? How long does the ETT stay in? Twenty minutes, 30, 45, 60 or longer? Thinking about that in a different way, what does that translate into in terms of number of PPV breaths? Well at a rate of 60 breaths a minute that means 1800, 2700, 3600 and more breaths before the ETT is removed. I have often wondered if this in itself explains why InSurE seems to be repeatedly identified as being inferior to MIST. If you intubated, gave the surfactant and pulled the ETT out right away in all cases might the two techniques actually be equivalent. The question now really is how do we get past our tendencies and embrace a change in practice that by design will not allow us to delivery any positive pressure breaths?!

In 2015 the Pediatric Endocrine Society (PES) published new recommendations for defining and managing hypoglycaemia in the newborn. A colleague of mine and I discussed the changes and came to the conclusion that the changes suggested were reasonable with some “tweaks”. The PES suggested a change from 2.6 mmol/L (47 mg/dL) at 48 hours of age as a minimum goal glucose to 3.3 mmol/L (60 mg/dL) as the big change in approach. The arguments for this change was largely based on data from normal preterm and term infants achieving the higher levels by 48-72 hours and some neuroendocrine data suggesting physiologically, the body would respond with counter regulatory hormones below 3.3 mmol/L. As it turned out, we were “early adopters” as we learned in the coming year that no other centre in Canada had paid much attention to the recommendations. The inertia to change was likely centred around a few main arguments. 1. How compelling was the data really that a target of 2.6 and above was a bad idea? 2. Fear! Would using a higher threshold result in many “well newborns” being admitted to NICU for treatment when they were really just experiencing a prolonged period of transitional hypoglycaemia. 3. If its not broken don’t fix it. In other word, people were resistant to change itself after everyone was finally accustomed to algorithms for treatment of hypoglcyemia in their own centres. What effect did it actually have? My colleagues along with one of our residents decided to do a before and after retrospective comparison to answer a few questions since we embraced this change. Their answers to what effect the change brought about are interesting and therefore at least a in my opinion worth sharing. If any of you are wondering what effect such change might have in your centre then read on! Skovrlj R, Marks S and C. Rodd published Frequency and etiology of persistent neonatal hypoglycemia using the more stringent 2015 Pediatric Endocrine Society hypoglycemia guidelines. They had a total of 58 infants in the study with a primary outcome being the number of endocrine consults before and after the change in practice. Not surprisingly as the graph demonstrates the number went up. Once the protocol was in place we went from arbitrary consults to mandatory so these results are not surprising. What is surprising though is that the median critical plasma glucose was 2.2 mmol/L, with no significant difference pre or post (2.0 mmol/L pre versus 2.6 mmol/L post, P=0.4) Ninety percent of the infants who were hypoglycemic beyond 72 hours of age were so in the first 72 hours. Of these infants, 90% were diagnosed with hyperinsulinemia. What this tells us is that those who are going to go on to have persistent hypoglycemia will demonstrate similar blood sugars whether you use the cutoff of 2.6 or 3.3 mmol/L. You will just catch more that present a little later using the higher thresholds. How would these kids do at home if discharged with true hyperinsulinemia that wasn’t treated? I can only speculate but that can’t be good for the brain… Now comes the really interesting part! Of the total infants in the study, thirteen infants or 40% had plasma glucose values of 2.6 to 3.2 mmol/L at the time of consultation after November 2015. Think about that for a moment. None of these infants would have been identified using the old protocol. Nine of these infants went on to require treatment with diazoxide for persistent hyperinsulinemia. All of these infants would have been missed using the old protocol. You might ask at this point “what about the admission rate?”. Curiously an internal audit of our admission rates for hypoglycemia during this period identified a decline in our admission rates. Concurrent with this change we also rolled out the use of dextrose gels so the reduction may have been due to that as one would have expected admission rates to rise otherwise. The other thing you might ask is whether in the end we did the right thing as who says that a plasma blood glucose threshold of 3.3 mmol/L is better than using the tried and true 2.6 mmol/L cutoff? While I don’t have a definitive answer to give you to that last question, I can leave you with something provocative to chew on. In the sugar babies study the goal glucose threshold for the first 7 days of life was 2.6 mmol/L. This cohort has been followed up and I have written about these studies before in Dextrose gel for hypoglycemia. Safe in the long run? One of the curious findings in this study was in the following table. Although the majority of the babies in the study had only mild neurosensory impairment detectable using sophisticated testing the question is why should so many have had anything at all? I have often wondered whether the goal of keeping the blood sugar above 2.6 mmol/L as opposed to a higher level of say 3.3 mmol/L may be at play. Time will tell if we begin to see centres adopt the higher thresholds and then follow these children up. I don’t know about you but a child with a blood sugar of 2.7 mmol/L at 5 or 6 days of age would raise my eyebrow. These levels that we have used for some time seem to make sense in the first few days but for discharge something higher seems sensible.

Use of caffeine in the NICU as a treatment for apnea of prematurity is a topic that has certainly seen it’s fair share of coverage on this blog. Just when you think there is an aspect of treatment with caffeine that hasn’t been covered before, along comes a new paper to change my mind. The Caffeine for Apnea of Prematurity study or CAP, demonstrated that caffeine given between 3-10 days of age reduced the incidence of BPD in those treated compared to those receiving placebo. As an added benefit, in follow-up studies of these patients there appeared to be a benefit to neurodevelopmental outcomes as well at 18-21 months but this was lost by school age with groups being equivalent. In recent years evidence has mounted that starting caffeine earlier in the time course (<3 days and in many cases in the first hour after birth) has led to less need for intubation and BPD. What has really not been known though is whether the use of caffeine in this way might have any long term benefits aside from these short term outcomes. Dr. Abhay Lodha from Calgary and a group of researchers led by Prakesh Shah from the Canadian Neonatal Network using our robust Canadian network data have tried to answer this with their paper Early Caffeine Administration and Neurodevelopmental Outcomes in Preterm Infants The group studied were <29 weeks’ gestation born between April 2009 and September 2011 and admitted to Canadian Neonatal Network centres. As defined in the paper “Neonates who received caffeine were divided into early- (received within 2 days of birth) and late-caffeine (received after 2 days of birth) groups. The primary outcome was significant neurodevelopmental impairment, defined as cerebral palsy, or a Bayley Scales of Infant and Toddler Development, Third Edition composite score of <70 on any component, hearing aid or cochlear implant, or bilateral visual impairment at 18 to 24 months’ corrected age.” There were 2018 neonates included in the analysis with 1545 in the early group and 563 in the late. It is worth noting that there were 473 infants lost to follow-up meaning that there was about an 80% follow-up rate. Looking at the characteristics of those infants lost to follow-up there were no striking differences that one would expect between them and the group followed. What did they find? The odds of BPD (aOR 0.61; 95% CI 0.45–0.81), PDA (aOR 0.46; 95% CI 0.34–0.62), and Severe Neurologic Injury – parenchymal injury or GR III/IV IVH or PVL (aOR 0.66; 95% CI 0.45–0.97) were reduced in the early- caffeine group. The primary outcome was also found to be significantly different as per the table below demonstrating the odds after logistic regression analysis. So early caffeine seems to be good. Is that all then? I am very happy to see these results but a few questions remain. Before we get too enthusiastic, I find myself thinking back to the early 2000s after the initial CAP results showed an apparent difference in outcome. The question is whether the reduction in odds seen here for the primary outcome will persist as these children age. Will we see a tendency for the differences to vanish as these children enter school age? I suspect we might but that doesn’t mean all is lost here. What the authors have demonstrated clearly is that early caffeine is not harmful as there is no suggestion of those infants exposed to caffeine so shortly after birth fare worse than those treated later. Also as the authors state, what isn’t clear is how caffeine works to decrease the risk of developmental impairment. In the discussion they offer some insightful thoughts as to what may be at play and I agree that certainly an anti-inflammatory effect may be responsible for some of the effect. I do wonder though if one could tie the reductions to the lower likelihood of BPD. Development of BPD has been shown many times over to be associated with worse developmental outcomes. Aside from the anti-inflammatory effect mentioned, could the avoidance of early intubation and therefore reduced risk of BPD from positive pressure ventilation be the reason? In the end if the results persistent into school age, the reason won’t really matter and I hope it does. Will see what happens when we revisit this cohort in a few years but in the meantime I think this paper certainly confirms in my mind the need to give caffeine and make sure it’s provided early!

Apologies as I forget to embed it. https://www.ncbi.nlm.nih.gov/m/pubmed/30353079/

Recent statements by the American Academy of Pediatric’s, NICHD, the American College of Obstetricians and Gynecologists (ACOG), the Society for Maternal-Fetal Medicine (SMFM), and recommend selective approaches to mothers presenting between 22 0/7 to 22 6/7 weeks. The decision to provide antenatal steroids is only recommended if delivery is expected after 23 weeks. Furthermore the decision to resuscitate is based on an examination of a number of factors including a shared decision with the family. In practice this leads to those centres believing this is mostly futile generally not resuscitating or offering steroids while other more optimistic hospitals having higher rates of proactive (steroids and resuscitation) rates. Then there are other centres where the standard approach is proactive such as one in Uppsala, Sweden where this approach is used almost exclusively. What would happen then if one compared the outcome for infants born at 22 weeks between this hospital and another where a selective approach is generally offered. In this case you would have a lot of experience with resuscitating infants at 22 weeks and the other a fraction of all presenting as a few to many would receive compassionate care. This is exactly what has now happened. A Tale of Two Cities The University Children’s Hospital, Uppsala, Sweden has been compared retrospectively to Nationwide Children’s Hospital, Columbus, Ohio, USA (NCH) with respect to survival and outcomes for their infants born at 22 weeks. The paper by Backes CH et al entitled Outcomes following a comprehensive versus a selective approach for infants born at 22 weeks of gestation tells a very interesting story about the power of belief or faith that one can accomplish something if they set their mind to it. The authors examined a period from 2006-2015, dividing this time into two epochs with the first being 2006-2010 to account for differing practices and resources over time. Given that Uppsala took a proactive approach to all of their 40 live born infants during this time, it provided an opportunity to look at the 72 infants who were live born in the Ohio and examine their differences. In Ohio the approach was as follows; 16 (22%) received proactive care, 18 (25%) received inconsistent care (steroids but no resuscitation), and 38 (53%) received comfort care. In other words, although the total number of infants live born in Ohio was almost double that of Uppsala, only 16 were proactively treated in Ohio compared to all 40 in Uppsala. The differences in outcome are striking Survival in delivery room: (38/40, 95% vs 12/16, 75%; P = 0.049) Provision of delivery room surfactant: (40/40, 100% vs 9/16, 56%; P<0.01) Survival at 24 h (37/40, 93% vs. 9/16, 56%; P < 0.01). Survival to 1 year (21/40, 53% vs. 3/16, 19%; P < 0.05). Among the infants treated proactively, median age of death (17 postnatal days at range 0 h–226 days vs. 3 postnatal hours at NCH, range 0 h–10 days; P < 0.01). All surviving infants had BPD All infants surviving to initial hospital discharge were alive at 18 months’ postnatal age. With respect to long term outcome the authors note: “Outpatient follow-up (qualitative or non-qualitative neurodevelopmental testing) was available in 26 out of 27 infants (96%) Eleven of the 26 (42%) were unimpaired, and all unimpaired infants were in the UUCH cohort. Among the 15 infants with impairment at UUCH, 3 had mild impairment and 12 had moderate or severe impairment. All surviving infants at NCH had moderate or severe impairment.” A word about antenatal steroids as well. In Uppsala 85% of mothers received 2 doses of antenatal steroids vs 25% in Ohio. People sometimes question whether ANS at this age are effective. It is interesting to note that 44% of babies in the Ohio group vs 3% p<0.01 received chest compressions +/- epinephrine in the delivery room. Might this explain the better state of some of these infants at birth? The Power of Belief When I do rounds I often remark that try as we might we can’t will babies to do better. I also commonly say however that we need to be optimistic and although I am accused of seeing the world through rose coloured glasses I think there is an important lesson to be learned from this study. This comparison is really a contrast between a system that believes they can do a good thing for these families by actively promoting a proactive approach vs a system in which I imagine a reluctant approach exists even for those infants where a proactive plan is enacted. One sign of this might be that in Sweden 100% of these deliveries had a Neonatologist present vs 75% in the US. It could be due to other factors such as ability of the Neo to get in within time of the delivery however rather than a sign they didn’t feel they were needed due to futility. There is evidence as well that the aggressiveness of the proactive approach also differs between the two sites based on a couple observations. The first is the rate of surfactant provision in the delivery room which was 100% in Sweden but only 56% in the US. The other thing of note is the time of death for those who did not survive. The median time of death in the US was 3 hours vs 17 days in Uppsala. What does this tell us about the approaches? I would imagine (although the numbers are small) that the teams in the US were much more likely to lose hope (or faith) and withdraw early while the other centre possibility motivated by their past successes pushed forward. Remarkably, although one might think that the teams in Uppsala were simply creating significantly impaired survivors, 42% of the survivors were unimpaired from a developmental standpoint in follow-up. All surviving infants though from Ohio had moderate to severe impairment. What this story may also really be about is practice. The reality is that the team in Sweden had over twice the exposure to such infants over time. Although the number presenting at this GA was higher, the ones that actually were resuscitated and given steroids was less than half. One cannot take away though that Uppsala in the end demonstrated that a proactive approach is definitely not futile. Not only can these children survive but almost half will be developmentally intact. We must acknowledge as well though that since this is a retrospective study there may be factors that may have affected the results. As the saying goes “Individual results may vary”. Are the teams the same in both centres in terms of number of Neonatologists? Are there more residents caring for these infants vs fellows? Are the resources the same? What about proximity of the Neonatologist to the hospital? There are other factors such as cohesiveness of the team and communication between team members that may be influencing the results. In the end though, this is a story of a team that believed it could and did. Perhaps seeing the world through rose coloured glasses is not such a bad thing in the end.

Look around an NICU and you will see many infants living in incubators. All will eventually graduate to a bassinet or crib but the question always is when should that happen? The decision is usually left to nursing but I find myself often asking if a baby can be taken out. My motivation is fairly simple. Parents can more easily see and interact with their baby when they are out of the incubator. Removing the sense of “don’t touch” that exists for babies in the incubators might have the psychological benefit of encouraging more breastfeeding and kangaroo care. Both good things. Making the leap For ELBW and VLBW infants humidity is required then of course they need this climate controlled environment. Typically once this is no longer needed units will generally try infants out of the incubator when the temperature in the “house” is reduced to 28 degrees. Still though, it is not uncommon to hear that an infant is “too small”. Where is the threshold though that defines being too small? Past research studies have looked at two points of 1600 vs 1800g for the smallest of infants. One of these studies was a Cochrane review by New K, Flenady V, Davies MW. Transfer of preterm infants for incubator to open cot at lower versus higher body weight. Cochrane Database Syst Rev 2011;(9). This concluded that early transition was safe for former ELBWs at the 1600g weight cut off. What about the majority of our babies? While the ELBW group takes up a considerable amount of energy and resources the later preterm infants from 29 to 33 6/7 weeks are a much larger group of babies. How safe is this transition for this group at these weights? Shankaran et al from the NICHD published an RCT on this topic recently; Weaning of Moderately Preterm Infants from the Incubator to the Crib: A Randomized Clinical Trial. The study enrolled Infants in this gestational age range with a birth weight <1600g were randomly assigned to a weaning weight of 1600 or 1800 g. Within 60 to 100 g of weaning weight, the incubator temperature was decreased by 1.0°C to 1.5°C every 24 hours until 28.0°C. Weaning to the crib occurred when axillary temperatures were maintained 36.5°C to 37.4°C for 8 to 12 hours. Clothing and bedcoverings were standardized. The primary outcome was LOS from birth to discharge. What did they find? A total of 366 babies were enrolled (187 at 1600g and 179 at 1800g. Baseline characteristics of the two groups revealed no statistical differences. Mean LOPS was a median of 43 days in the lower and 41 days in the higher weight group (P = .12). After transition to a crib weight gain was better in the lower weight group, 13.7 g/kg/day vs 12.8 g/kg/ day (P = .005). Tracking of adverse events such as the incidence of severe hypothermia did not differ between groups. The only real significant difference was a better likelihood of weaning from the incubator in the higher group at 98% success vs 92% on the first attempt. Putting. That in perspective though, a 92% success rate by my standards is high enough to make an attempt worthwhile! Concluding thoughts The authors have essentially shown that whether you wean at the higher or lower weight threshold your chances of success are pretty much the same. Curiously, weight gain after weaning was improved which seems counter intuitive. I would have thought that these infants would have to work extra hard metabolically to maintain their temperature and have a lower weight gain but that was not the case. Interestingly, this finding has been shown in another study as well; New K, Flint A, Bogossian F, East C, Davies MW. Transferring preterm infants from incubators to open cots at 1600 g: a multicentre randomised controlled trial. Arch Dis Child Fetal Neonatal Ed 2012;97:F88-92. Metabolic rate has been shown to increase in these infants but skin fold thickness has been shown to increase as well in infants moved to a crib. How these two things go together is a little beyond me as I would have thought that as metabolic rate increases storage of tissue would slow. Not apparently the case but perhaps just another example of the bodies ability to overcome challenges when put in difficult situations. A case maybe of “what doesn’t kill you makes you stronger?” The authors do point out that the intervention was unmasked but the standardization of weaning procedure and garments used in the cribs should have overcome that. There were 36% of parents who did not consent to the study so their inclusion could have swayed the results perhaps but the sample size here was large despite that. That the final results agree with findings in ELBW infants suggests that the results are plausible. What I think this study does though is tell us overall that weaning at a smaller weight is at least alright to try once one is at minimal settings in an incubator. Will this change your units practice? It is something that at least merits discussion.

As a Neonatologist, there is no question that I am supportive of breast milk for preterm infants. When I first meet a family I ask the question “are you planning on breastfeeding” and know that other members of our team do the same. Before I get into the rest of this post, I realize that while breast milk may be optimal for these infants there are mother’s who can’t or won’t for a variety of reasons produce enough breast milk for their infants. Fortunately in Manitoba and many other places in the world breast milk banks have been developed to provide donor milk for supporting these families. Avoidance of formula in the early days to weeks of a ELBWs life carries benefits such as a reduction in NEC which is something we all want to see. Mother’s own milk though is known to have additional benefits compared to donor milk which requires processing and in so doing removes some important qualities. Mother’s own milk contains more immunologic properties than donor including increased amounts of lactoferrin and contains bioactive cells. Growth on donor human milk is also reduced compared to mothers’ own milk and lastly since donor milk is obtained from mothers producing term milk there will be properties that differ from that of mothers producing fresh breast milk in the preterm period. I have no doubt there are many more detailed differences but for basic differences are these and form the basis for what is to come. The Dose Response Effect of Mother’s Own Milk Breast milk is a powerful thing. Previous studies on the impact of mother’s own milk (MOM) have shown that with every increment of 10 mL/kg/d of average intake, the risk of such outcomes as BPD and adverse developmental outcomes are decreased. In the case of BPD the effect is considerable with a 9.5% reduction in the odds of BPD for every 10% increase in MOM dose. With respect to developmental outcome ach 10 mL/kg/day increase in MOM was associated with a 0.35 increase in cognitive index score. One of the best names for a study has to be the LOVE MOM study which enrolled 430 VLBW infants from 2008-2012. The results of this study Impact of early human milk on sepsis and health-care costs in very low birth weight infants.indicated that with incremental increases of 10 mL/kg of MOM reductions in sepsis of 19% were achieved and in addition overall costs were reduced. The same group just published another paper on this cohort looking at a different angle. NICU human milk dose and health care use after NICU discharge in very low birth weight infants. This study is as described and again looked at the impact of every 10 mL/kg increase in MOM at two time points; the first 14 and the first 28 days of life. Although the data for the LOVE MOM trial was collected prospectively it is important to recognize how the data for this study was procured. At the first visit after NICU discharge the caregiver was asked about hospitalizations, ED visits and specialized therapies and specialist appointments. These were all tracked at 4 and 8 months of corrected age were added to yield health care utilization in the first year, and the number of visits or provider types at 4, 8, and 20 months of corrected age provided health care utilization through 2 years. What were the results? “Each 10 mL/kg/day increase in HM in the first 14 days of life was associated with 0.26 fewer hospitalizations (p = 0.04) at 1 year and 0.21 fewer pediatric subspecialist types (p = 0.04) and 0.20 fewer specialized therapy types (p = 0.04) at 2 years.” The results at 28 days were not statistically significant. The authors reported both unadjusted and adjusted results controlling for many factors such as gestational age, completion of appointments and maternal education to name a few which may have influenced the results. The message therefore is that the more of MOM a VLBW is provided in the first 14 days of life, the better off they are in the first two years of life with respect to health care utilization. That even makes some sense to me. The highest acuity typically for such infants is the first couple of weeks when they are dealing with RDS, PDA, higher oxygen requirements etc. Could the protective effects of MOM have the greatest bang for your buck during this time. By the time you reach 28 days is the effect less pronounced as you have selected out a different group of infants at that time point? What is the weakness here though? The biggest risk I see in a study like this is recall bias. Many VLBW infants who leave the NICU have multiple issues requiring many different care providers and services. Some families might keep rigorous records of all appointments in a book while others might document some and not others. The big risk here in this study is that it is possible that some parents overstated the utilization rates and others under-reported. Not intentionally but if you have had 20 appointments in the first eight months could the number really by 18 or 22? Another possibility is that infants receiving higher doses of MOM were healthier at the outset. Maternal stress may decrease milk production so might mothers who had healthier infants have been able to produce more milk? Are healthier infants in the first 14 days of life less likely to require more health care needs in the long term? How do we use this information? In spite of the caveats that I mentioned above there are multiple papers now showing the same thing. With each increment of 10 mL/kg of MOM benefits will be seen. It is not a binary effect meaning breastfed vs not. Rather much like the medications we use to treat a myriad of conditions there appears to be a dose response. It is not enough to ask the question “Are you intending to breastfeed?”. Rather it is incumbent on all of us to ask the follow-up question when a mother says yes; “How can we help you increase your production?” if that is what the family wants>

Much has been written on the topic of cord clamping. There is delayed cord clamping of course but institutions differ on the recommended duration. Thirty seconds, one minute or two or even sometimes three have been advocated for but in the end do we really know what is right? Then there is also the possibility of cord milking which has gained variable traction over the years. A recent review was published here. Take the Guessing Out of the Picture? Up until the time of birth there is very little pulmonary blood flow. Typically, about 10% of the cardiac output passes through the lungs and the remained either moves up the ascending aorta or bypasses the lungs via the ductus arteriosus. After birth as the lung expands, pulmonary vascular resistance rapidly decreases allowing cardiac output to take on the familiar pattern which we all live with. Blood returning from the systemic venous circulation no longer bypasses the lung but instead flows through pulmonary capillaries picking up oxygen along the way. One can imagine then that if a baby is born and the cord is clamped right away, blood returning from the systemic circulation continues to bypass the lung which could lead to hypoxemia and reflexive bradycardia. This has been described previously by Blank et al in their paper Haemodynamic effects of umbilical cord milking in premature sheep during the neonatal transition. A group of researchers from the Netherlands published a very interesting paper Physiological-based cord clamping in preterm infants using a new purpose-built resuscitation table: a feasibility study this month. The study centres around a resuscitation table called the Concord that is brought to the mother for resuscitation after birth. The intervention here was applied to infants 26 to 35 weeks gestational age. The cord was clamped after each of the following was achieved for an infant indicating successful transition with opening of the lung and establishment of an FRC. 1. Establishment of adequate breathing (average tidal volume ≥4 mL/kg) on CPAP. They used a mask capable of measuring expired tidal volumes. 2. HR above 100 bpm 3. SpO2 above 25th percentile using FiO2 <0.4 In this way, the cord was only clamped once the baby appeared to have physiologically made the transition from dependence on umbilical cord blood flow to ventilation perfusion matching in the lung. Although 82 mothers consented only 37 preterm infants were included in the end. Exclusion criteria were signs of placental abruption or placenta praevia, signs of severe fetal distress determined by the clinician and the necessity for an emergency caesarean section ordered to be executed within 15 min. This really was a proof of concept study but the results are definitely worth looking at. How Did These Babies Do? There are many interesting findings from this study. The mean time of cord clamping was 4 minutes and 23 seconds (IQR 3:00 – 5:11). Heart rate was 113 (81–143) and 144 (129–155) bpm at 1 min and 5 min after birth. Only one patient developed bradycardia to <60 BPM but this was during a mask readjustement. The main issue noted as far as adverse events was hypothermia with a mean temperature of 36.0 degrees at NICU admission. Almost 50% of infants had a temperature below 36 degrees. Although the authors clearly indicate that they took measures to prevent heat loss it would appear that this could be improved upon! What stands out most to me is the lengthy duration of cord clamping. This study which used a physiologic basis to determine when to clamp a cord has demonstrated that even at 1 minute of waiting that is likely only 1/4 of the time needed to wait for lung expansion to occur to any significant degree. I can’t help but wonder how many of the patients we see between 26-35 weeks who have a low heart rate after delivery might have a higher heart rate if they were given far more time than we currently provide for cord clamping. I can also see why cord milking may be less effective. Yes, you will increase circulating blood volume which may help with hemodynamic stability but perhaps the key here is lung expansion. You can transfuse all the blood you want but if it has nowhere to go just how effective is it? As we do more work in this area I have to believe that as a Neonatal community we need to prepare ourselves for the coming of the longer delay for cord clamping. Do we need to really have the “Concord” in every delivery or perhaps it is time to truly look at durations of 3-4 minutes before the team clamps the cord. Stay tuned!

As the saying goes, sometimes less is more. In recent years there has been a move towards this in NICUs as the benefits of family centred care have been shown time and time again. Hi tech and new pharmaceutical products continue to develop but getting back to the basics of skin to skin care for many hours and presence of families as an integral team member have become promoted for their benefits. The fetus is a captive audience and hears the mother's heart beat and voice after the development of hearing sometime between 24-26 weeks gestational age. This is a normal part of development so it would stand to reason that there could be a benefit to hearing this voice especially after hearing has developed and the fetus has grown accustomed to it. Hospital including my own have developed reading programs for our patients and some companies have developed speakers in isolettes designed to limit the maximum decibel to 45 but allowing parents to make recordings of their voices. Music may be played through these speakers as well but today we will focus on the benefit of voice. Could reading to your baby reduce apnea of prematurity? This is the question that Scala M et al sought to answer in their paper Effect of reading to preterm infants on measures of cardiorespiratory stability in the neonatal intensive care unit. This was a small prospective study of the impact of parental reading on cardiorespiratory stability in preterm NICU infants. Eighteen patients were enrolled who were born between 23-31 weeks gestation. The study was carried out when the babies were between 8-56 days old at a mean postnatal age of 30 weeks. Each patient served as their own control by comparing episodes of oxygen desaturation to <85% during pre-reading periods (3 hours and 1 hour before) to during reading and then 1 hour post reading. Parents were asked to read or create a recording lasting a minimum of 15 min but up to 60 min of recorded reading. The parents were offered a standard set of books that had a certain rhythm to the text or could choose their own. Recorded reading was played for infants up to twice per day by the bedside nurse. While it was small in number of patients the authors point out that the total exposure was large with 1934 min of parental bedside reading analyzed (range 30–270 min per infant, mean 123, median 94 min). Patients could be on respiratory support ranging from ventilators to nasal cannulae. Was it effective? It certainly was. I should mention though that the authors excluded one patient in the end when it was found that they failed their hearing screen. Arguably, since the infant could not have benefited from the intervention effect this makes sense to me. As shown from table 3 there was a statistical reduction in desaturation events during the reading period which was sustained in terms of a downward trend for one hour after the intervention was completed. In case you are asking was the difference related to oxygen use the answer is no. There was no difference in the amount of oxygen provided to patients. While the events were not eliminated they were certainly reduced. The other point worth mentioning is that there appears to be a difference between live (through open portholes) vs prerecorded reading (through a speaker in the isolette). Now for a little controversy Does source of the reading matter? The authors found that maternal had a greater effect than paternal voice. As a father who has read countless books to his children I found this a little off-putting. As a more objective critic though I suppose I can buy the biologic plausibility here. I suspect there is an independent effect of voice having a positive impact on development. If we buy the argument though that the voice that the fetus has most been accustomed to is the mothers, then the findings of an augmented effect of the maternal voice over fathers makes some sense. I will have to put my ego aside for a moment and acknowledge that the effect here could be real. There will no doubt need to be larger studies done to drill down a number of questions such as what is the ideal type of reading, duration, rhythmic or non etc but this is a great start. I also think this falls into the category of "could this really be a bad thing?". Even if in the end no benefit is shown to this type of intervention, the potential for family bonding with their preterm infant alone I think is cause for embracing this intervention. Lastly, with the move to single patient rooms there is one study that demonstrated the isolation encountered from infrequent contact with their newborn can have a long lasting effect on development. The article by Pineda RG et al Alterations in brain structure and neurodevelopmental outcome in preterm infants hospitalized in different neonatal intensive care unit environments. had a mean parental visitation of 19 +/- 19 hours a week or a little over 2 hours a day but with a very large standard deviation meaning many infants had almost no visitation. The message here is that while quiet is good for infant development, too much can be a bad thing. Maybe live reading or even recordings are a way around that.