Delivery room interventions for the profoundly immature: what are we doing, what should we do?

I still haven’t found the best term for babies who are born so immature that their chances of survival are significantly reduced. Extremely Low Gestational Age Newborn, or ELGAN is a term which is not pretty but has the advantage of being accurate and not being associated with any value judgement, it is, however, now very strongly associated with Dr Alan Leviton (and many others)’s cohort study, almost becoming a trade mark! “Threshold of viability”, (or infants born at the…) has the disadvantage of being a moving target and not being clear as to how viability is determined; as we will soon see, if you decide a baby in this gestational age range is not viable, they will die. “The periviable period” is, I think a reasonable term for the time between 20 and 24 weeks, but I really don’t like “periviable neonates” for the same reasons I just mentioned, and “infants born during the periviable period” is unwieldy. Maybe “profoundly immature” is a better term, no values involved, and clear to everyone what we are talking about…

Two very recent publications and their accompanying editorials are worth discussing. They have different methods and conclusions as you will see:

The first is a study from France, part of the EPIPAGE-2 study. Perlbarg J, et al. Delivery room management of extremely preterm infants: the EPIPAGE-2 study. Archives of disease in childhood Fetal and neonatal edition. 2016.

This study was a high quality prospective cohort study of very preterm deliveries in all but one of the administrative regions of France. To clarify, France is divided into 22 metropolitan regions (that is, mainland France) and 4 overseas regions (Guadeloupe, Martinique, La Réunion, et Guyane (French Guyana)), or at least it was, as the number of regions has been decreased recently, it seems. All but one of the metropolitan regions was included in EPIPAGE-2, and all of the overseas regions. The timing of inclusion overlapped but wasn’t exactly the same for each region, which is a shame; but given the enormous nature of this study we can forgive a few logistic problems.

The protocol publication (Ancel PY, Goffinet F. EPIPAGE 2: a preterm birth cohort in France in 2011. BMC pediatrics. 2014;14:97) notes the following :

EPIPAGE 2 is a population-based prospective study scheduled to follow children up to the age of 12 years. Eligible participants include all infants live born or stillborn and all terminations of pregnancy between 22 and 31 completed weeks of gestation in all the maternity units in 25 French regions (21 of the 22 metropolitan regions and 4 overseas regions) during the inclusion period. The only region that did not participate accounted for 18 415 births in 2011, i.e., 2.2% of all births in France

The babies in the study were born between May and December 2011, in some regions the time periods of data collection were not exactly the same, but they all overlapped.

This particular publication is about what happened in the delivery room for babies who were thought to be between 22 and 26 weeks gestation. It includes just over 2000 births, and is a good description of French practices during that period.

One of the problems with large regional cohort studies like this is that they include very acute unexpected extremely preterm deliveries in small general medical centers, as well as controlled deliveries in tertiary teaching hospital centers. There are many layers of subtlety that are difficult to grasp from afar.

Nevertheless, there are a number of findings worthy of discussion. At 22 weeks gestation there were 421 deliveries, of which 52 were “terminations of pregnancy” we don’t know from the paper what the indications for the termination were; (some “terminations” are performed because of preterm labour, which is quite different to terminations performed because of life-threatening malformations, for example). Of the remaining pregnancies, most led to stillbirth (74%, of the original group, but 85% after excluding terminations of pregnancy) and, among the others, only one of the live born babies received active intervention with oxygen and intubation, that baby died, leading to a survival of zero.

Even stillbirth, however, is not necessarily a hard endpoint; what I mean is that an attitude of active management of profoundly immature delivery will dramatically increase the number of babies born alive, compared to those born without a heart rate. It is also the case that some babies who are classified as stillbirths may be apneic, and, as a decision for comfort care has already been made, no-one seeks a heart rate. They may thus be resuscitatable, but are classified as stillborn.

If we try and contrast these results to the Swedish national cohort (EXPRESS), that study excluded pregnancy terminations, and at 22 weeks gestation there were 142 deliveries with 91 still births or 64% were stillborn, of the 51 liveborn infants there were 23 admitted to the NICU with 6 surviving to discharge.

There are differences between the 2 cohorts at 23 weeks also, in the EXPRESS study there were 183 deliveries and 82 were stillbirths, or 45%; they also report the intrapartum deaths, that is those stillbirths for whom the baby was known to have had a heart rate prior to labour, which were 19, or 10%. There were 16 deaths in the delivery room, leaving 81 admitted to the NICU, with 53 survivors (or 65% of NICU admissions). The EXPRESS study does not give the proportion of babies who had a decision for comfort care before delivery, but almost all of those born at a level 3 hospital had a neonatologist present at birth, and most were intubated.

In the French cohort there were 361 deliveries at 23 weeks that were not terminations, 270 were stillbirths, or 75%. That leaves 89 who were born alive, most did not have active intervention in the delivery room, seven of the babies were admitted to the NICU and 1 survived.

At 24 weeks there are still major differences between the 2 cohorts, many more stillbirths, and delivery room deaths, and NICU deaths, in the French cohort than the Swedish.

At 25 weeks there are smaller differences in the delivery room, but NICU deaths remained higher, 65% survival of NICU admissions at 25 weeks in France compared to 82% in Sweden.

In the French study, they examined what factors were associated with the decision-making regarding withholding or withdrawing intensive care, in addition to gestational age, babies under 600g were more likely than larger babies to have care withheld or withdrawn, babies from IVF were less likely to have this, but there was no difference between boys and girls. We know that smaller babies at any gestational age have lower survival, so to take that into account in decision-making is reasonable, but IVF has no known effect on survival, and sex certainly does, effect at least as important as birth weight. Which points out that decision-making is driven by values and not just by data, even if national guidelines have, until recently, uniquely spoken about the risks of death or disability as the driving force for decision-making.

The authors of the article point out that survival rates to discharge are lower in France, than in Sweden, the USA, Japan or Australia, at 23 up to 26 weeks gestation. Part of which difference is associated with the relative rarity of active intensive care below 25 weeks, but intensive care was given to the majority of babies at 25 and 26 weeks, yet survival rates were still lower. The authors speculate that later withdrawal of intensive care may be more frequent, given how frequent it is before NICU admission in the profoundly immature, and also that places who give intensive care to the most profoundly immature babies have lower mortality for more mature infants. That second explanation is supported by results from the NICHD NRN (Smith PB, et al. Approach to infants born at 22 to 24 weeks’ gestation: relationship to outcomes of more-mature infants. Pediatrics. 2012;129(6):e1508-16), and I think it likely that both are important.

The accompanying editorial Janvier A, Lantos J. Delivery room practices for extremely preterm infants: the harms of the gestational age label. Archives of disease in childhood Fetal and neonatal edition. 2016;101(5):F375-6. points out the same issues and wonders if there is any other place in modern medicine where interventions are universally denied in one high-income country, and almost universally applied in another.

I have asked the same thing about these differences, which also occur even within the USA. Is there any other condition in modern medicine, where one university center has 0% rates of intervention, and another, even in the same network, has 100%? And yet all of us claim to be practicing shared decision-making! I think the share is clearly not equally divided.

The second article is a regional study using administrative databases from New South Wales, Australia. (Haines M, et al. Population-based study shows that resuscitating apparently stillborn extremely preterm babies is associated with poor outcomes. Acta Paediatrica. 2016. Which is the kind of title that makes me sarcastically say “what a surprise!”) Between 1998 and 2011 they examined the outcomes of over 2000 babies of 22 to 27 weeks and 6 days who were born with a 1 minute Apgar of 0.  As far as I can tell, and this still isn’t quite clear to me after re-reading, the babies were classified as stillborn or live-born by the local personnel at the time who filled in the official  documents. The abstract states “We classified 2173 infants….. as stillborn” but I don’t see any methods for the authors to have done that. Of the infants classified as stillborn there were 40 who had an attempt at resuscitation, none were admitted to NICU, one surviving 51 days, but none surviving to discharge. I thought at first when I saw that all the stillborn resuscitated babies had died, that a baby who never responded during resuscitation and never had a heart rate might be considered to be stillborn, I think it’s weird that a baby who lives for 51 days would be called stillborn! I guess when you look at over 2000 records you are bound to find weird things, some of which might just be errors.

We also don’t know from these data which babies had a fetal heart rate detected in the hospital before delivery, and how many of the non-resuscitation babies were already known to have deceased in utero.

Of the 89 infants who were classified as live-born 48 had a resuscitation attempt, 13 were stabilized enough for NICU admission and 11 were discharged alive. The survivors ranged from 23 to 27 weeks gestation.

None of the infants in this study who still had an APGAR recorded as 0 at 5 minutes of age survived.

The conclusion of the study states that even with resuscitation attempted, “almost all of the babies died”. I don’t agree that 11 survivors out of 88 resuscitation attempts is “almost all”. The comparison group, babies with 1 minute Apgar 0 and no resuscitation attempt, had zero survivors.

The data on the lack of response when the babies were still pulseless at 5 minutes is useful I think, it is consistent with a somewhat different data set that we published a few years ago (Janvier A, Barrington KJ. The ethics of neonatal resuscitation at the margins of viability: informed consent and outcomes. The Journal of pediatrics. 2005;147(5):579-85) where we showed that if the babies at 23 weeks needed extensive resuscitation, and still were bradycardic by 3 minutes, they usually died, or may have survived but with major short-term complications. Extending this out to being pulseless at 5 minutes might give us enough certainty for these extremely preterm babies that they aren’t going to make it, and potentially stop resuscitative efforts.

La Gamma EF, et al. Resuscitation of potentially stillborn periviable neonates: who lives, who dies and who gets missed? Acta Paediatr. 2016;105(11):1252-4. The editorial accompanying the Australian study puts the results of the study differently; they state the following : “active resuscitation of ELGANs with a zero Apgar… increases survival”. They suggest that active intervention and a trial of therapy is the preferred approach for babies such as these, but that such an approach should be accompanied by an understanding by the neonatal team (which I hope includes the parents) and when futility is achieved. I think “futility” is not the best term to use here, it is indefinable and slippery. I would prefer that we just talk about frequent re-evaluations of the status of the baby, with an honest re-consideration of the goals of care. Trying to pre-establish limits of interventions or of acceptable complications is helpful but difficult, and also tends to slip away.

My take on these 2 articles is that, as I have said many times before, making a decision and having strict intervention guidelines based on gestational age alone makes no sense. We usually do not know gestational age with accuracy, and even if we did, there is a huge range of potential outcomes at any gestational age, which overlap by much more than 2 weeks. Babies with a significant chance of survival, taking into account all of the prognostic information available, should be offered a trial of therapy, which should include extensive delivery room resuscitation if required. What “significant chance” means is different for different families, and a major part of the antenatal consultation should be involved with establishing a relationship of trust with the parents and exploring their values in order to define what that means for them.

I’d encourage everyone to read also a new “viewpoint article” from 2 members of our team,  Gaucher N, Payot A. Focusing on relationships, not information, respects autonomy during antenatal consultations. Acta Paediatr. 2016.  which discuss the relational aspects of the antenatal consultation, based on research that has been done in Québec, and elsewhere, over the last several years, including the latest publication that I discussed recently on this blog.

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Oxygen, getting the dose right. Not so easy.

Preterm babies require differing concentrations of oxygen to maintain them within the optimal saturation range, which is clearly the low 90’s, from all the data we have so far (Saugstad OD, Aune D. Optimal Oxygenation of Extremely Low Birth Weight Infants: A Meta-Analysis and Systematic Review of the Oxygen Saturation Target Studies. Neonatology. 2013;105(1):55-63.) Of course there are still many unknowns, such as the importance of intermittent hypoxia compared to persistently lower saturations, the importance of intermittent hyperoxia, which is not infrequent and may frequently follow apnea. How important is keeping the saturations stable? I think it probably is quite important, but extremely difficult to know, and difficult to achieve.

How do we make sure that preterm infants always get the dose of oxygen that will keep them in that range?

Many years ago there were publications about the development of servo-controlled oxygen blenders which were linked to transcutaneous oxygen electrodes. They never reached commercial exploitation.

Which has led to the current situation where oxygen saturation alarms are the most frequent alarms in the NICU, alarms which often require manual adjustment of oxygen dose, sometimes hundreds of times a day. There are now several servo-controlled oxygen dosing devices in various stages of development and exploitation.

I think these devices could be an enormous advance in neonatology, but there are a few things that will have to be addressed :

  1. How to ensure that the oxygen isn’t increased when a baby is apneic. If the baby isn’t breathing then increasing oxygen concentrations will be ineffective to improve saturations, and may well lead to fairly prolonged hyperoxia when they start breathing againvan (Zanten HA, et al. The risk for hyperoxaemia after apnoea, bradycardia and hypoxaemia in preterm infants. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2014). On the other hand, there may well be lung volume loss during an apnea and an increase in VQ mismatch, and a temporary increase in O2 needs during recovery (I am not sure this has ever been demonstrated, but it is a possibility) which means that the O2 should probably remain constant during the apnea, but then be programmed to be ready to increase when the baby starts to breathe again.
  2. The linked concern is how we will be sure that post-apneic hyperoxia isn’t worsened by servo-controllers. I think it is likely to be improved, with more rapid reduction to baseline requirements.
  3. How to ensure that periodic breathing isn’t intensified and prolonged by the servo-controller. Periodic breathing is a pattern of breathing that is driven by the peripheral chemoreceptor.  It is maintained by a phase-shift of stimulus (hypoxia) and response (increased respiratory drive consequent on increased chemoreceptor afferent activity), so when you examine recordings of babies with prolonged periodic breathing you will often see (depending on response times of all the elements in the system) that saturations are increasing when the baby is in the apneic phase and decreasing when the baby is breathing (Barrington KJ, Finer NN. Periodic breathing and apnea in preterm infants. Pediatr Res. 1990;27(2):118-21.) This happens because of the delays in the physiologic response system, in other words when a baby stops breathing it takes a while for the blood passing through the lungs to desaturate, even more time for that blood to reach the peripheral chemoreceptor (which is by the way the only part of the respiratory control system that responds directly to oxygen tension) and then more time again for the chemoreceptor responses to be translated into phrenic nerve activity. (and that explanation jumps over several intermediate steps). Periodic breathing can last for hours in some babies, and may be associated with large fluctuations in saturation.  I think there is a real chance that servo-regulated FiO2 could re-inforce these cycles, and might lead to prolonged repetitive desaturation/resaturation events. Which might (or might not) be harmful.
  4. The pulse oximeters will continue to have alarms set, can we use these new systems to make the alarms smarter? In the NICU when a baby in in room air there is no value to having a high saturation alarm, so the high alarm is usually switched off. If the baby has a transient desaturation and the oxygen is increased a little, what often happens is that the baby will recover back to high saturations, and, as the high alarm was switched off, the baby may over-saturate for prolonged periods of time. It shouldn’t be too difficult, once there is a link between the oximeter and the oxygen blender, to switch of the high alarm when the baby is in room air, and switch it back on again when the baby is receiving oxygen.

As a result of these concerns, I think that we do need to prove that servo-regulated oxygen devices improve clinical outcomes, or at least does not worsen them.

The stimulus from this blog post came from a new study published by the neonatal group from Tasmania, (Plottier GK, et al. Clinical evaluation of a novel adaptive algorithm for automated control of oxygen therapy in preterm infants on non-invasive respiratory support. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016).
using a novel system that they have developed, they studied 10 preterm infants on non-invasive support with a cross-over design, and showed a major reduction in time outside the oximetry target range. Their new system incorporates several potential improvements in the response algorithms.

An accompanying editorial from Christian Poets and Axel Franz is well worth reading also, it includes this interesting graphic which shows, firstly that there are more stories than I was aware of, for each study they show with the small horizontal lines, what the target saturations were, i.e. they were between the light and dark grey lines. Then they show what proportion of time the manual adjustment of FiO2 and the automated control of FiO2 were within the target range.


Some of their interesting thoughts about this situation, you can see that the proportion of time within target range for manual control was extremely variable, these are all small corss-over studies, so it may be differences in the patients that is the reason behind this. All the studies showed more time in target range, and the degree of improvement was quite variable also, with the new study having one of the greatest improvements in percentage in the target range.

The new study also showed very little time with extreme hypoxia (<80%) and very little time with extreme hyperoxia while receiving oxygen, all of which were statistically significantly better than manual adjustment.  The manual care periods were associated with more than 2 adjustments of oxygen of more than 1% per hour on average, the aut0matic by over 60 adjustments of more than 1% and about 600 adjustments per hour of at least 0.5%, which is the way the automated blender is controlled.

As I started off saying, I think this is going to be a major improvement in neonatal care, but as for many other things, we need to have some evidence of improved clinical outcomes, otherwise it will be difficult to get funding for the new equipment, installation and training that will be required.

Fortunately, as Poets and Franz note, there is a trial in the works for which funding has been approved. In the meantime continuing to improve the algorithms will be necessary.


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It’s only mild Encephalopathy; now can we stop worrying?

I learnt as a fellow that infants whose maximum grade of HIE was Sarnat 1, or mild, had normal outcomes. I recognized that the data to support that were limited, but one of the best older studies was by my mentor and friend Neil Finer, who together with Charlene Robertson organised the follow-up at 3.5 years of 226 babies with varying degrees of encephalopathy. (Robertson C, Finer NN. Term Infants With Hypoxic-Ischemic Encephalopathy: Outcome At 3.5 Years. Developmental Medicine & Child Neurology. 1985;27(4):473-84).

If we concentrate on the mild cases in that study, there were 79 who were evaluated for the presence of “handicap”; the definition of “handicap” used in that study included cerebral palsy of any severity, severe visual impairment or deafness, difficult to control epilepsy, or a score more than 3 SD below the population mean (100) on Stanford-Binet IQ tests. Using that definition, which picks out children whose condition has a significant impact on their lives, all the 79 mild encephalopathy cases were non-handicapped.

In contrast all the severe encephalopathy cases were either dead or “handicapped”, and the moderate cases had about 1/3 prevalence of “handicap”.

In those earlier studies Sarnat stage 1 refers to infants whose worst stage during their hospitalization was stage 1, children who deteriorate after the first few hours are not uncommon, and they would have been classified by their worst stage.

A recent publication from McGill describes short-term outcomes and MRI injury among infants who presented with mild encephalopathy, the study doesn’t include long-term follow-up, but there were a number of kids who had mild encephalopathy at presentation who had adverse clinical or MRI outcomes. (Gagne-Loranger M, et al. Newborns Referred for Therapeutic Hypothermia: Association between Initial Degree of Encephalopathy and Severity of Brain Injury (What About the Newborns with Mild Encephalopathy on Admission?). American journal of perinatology. 2016;33(2):195-202.) In this study there were 50 babies who had mild encephalopathy on admission, were not cooled and had an MRI. There were also 13 who had mild encephalopathy who were cooled, mostly because of aEEG abnormalities. Of the 50 not cooled babies, there were 20, (40%) who developed MRI abnormalities, including some very severe abnormalities, one of whom actually died of complications of HIE. Many of the babies who had MRI injuries had a worsening of their clinical status over the first couple of days of life, and none of those who were mild but were cooled because of aEEG abnormalities had MRI injuries.

Another fairly recent study from Parkland Memorial hospital described the short-term outcome of 89 babies who had acidosis at birth and were evaluated for the presence of encephalopathy. 69 of them had mild encephalopathy during the first 6 hours of life, (20 were normal) and of those 69 a substantial number had adverse short-term outcomes, which included later onset of seizures in 5, one of whom progressed to very severe findings and died of multi-organ failure. Others of them had feeding difficulties, persistent neurologic abnormalities at discharge, or abnormal MRI findings, for a total of 12 of the 69 with mild encephalopathy. The 20 with a normal exam were fine. Presumably, repeated encephalopathy exams would have found some progression in those who ended up with later abnormalities, and, of course, those with later seizures would automatically have been classified later on as having at least moderate encephalopathy.

A study just published on-line in Pediatrics has further data, (Murray DM, et al. Early EEG Grade and Outcome at 5 Years After Mild Neonatal Hypoxic Ischemic Encephalopathy. Pediatrics. 2016). This is a very well done prospective cohort study, all the babies were examined within  6 hours of birth by a single pediatric neurologist, all had 24 to 72 hour EEGs and there was a prospectively enrolled healthy full term comparison group who also had EEG (but only for 2 hours for obvious reasons). 53 babies with HIE were included, and 30 controls, the babies had been born before 2006 and were followed up to 5 years of age. The encephalopathy grade finally assigned was determined on the examination at 24 hours of age, which might not have been the same as the 6 hour grade, and may not be the same as the worst grade either.

The study shows a number of things, first of all the importance of having a comparison group. The comparison group had a Full Scale IQ of 117. So either the initial standardization of the test (WPPSI-III) no longer applies, or the controls were selectively of higher IQ than the Irish population, or (and this is my explanation) Irish babies are just smart. In comparison to the controls, the babies who were stage 1 HIE at 24 hours of age had lower IQ across all domains, and a mean FSIQ of very close to 100.


A Worse EEG grade at 6 hours was associated with poorer outcomes, EEGs all tended to improve or stay stable at 24 hours, and the grade of EEG abnormalities was more predictive at 24 hours than at 6.

So to summarize, infants who have stage 1, or mild, encephalopathy at 6 hours of age, when the decision is being made to cool them or not, do not have universally good outcomes. Many of them will have adverse outcomes, which can be predicted to some extent by: a later worsening of the clinical stage including later onset of seizures, or an abnormal aEEG or EEG, or persistence of stage 1 signs for more than 7 days (I didn’t talk about those data, they are older but appear reliable).

When comparing outcome studies in this group it is therefore important to know whether they are referring to the worst grade of HIE, or the grade at 6 hours, or at some other time point.

What to do about these babies? Starting hypothermia treatment later may actually have some effect, the 6 hour cut off that we use was rather arbitrary, and based on animal models with known timing and duration of the hypoxic ischemic insult and a fairly standard severe cerebral injury. Infants who have a mild encephalopathy and who start to deteriorate might therefore benefit from cooling started at 7, 8, 9 hours after insult.  But I presume there must be a limit, once those neurones are dead they aren’t coming back to life.  It seems that aEEG monitoring (and interpretation) for infants with mild encephalopathy is helpful in predicting which kids will progress to more severe short-term outcomes, according to, among other studies, the first study in this post, and in therefore deciding to proceed to cooling. If you can easily get a multi-channel EEG with expert interpretation as soon as the baby arrives, that is probably better than an aEEG.

The approach we have generally taken at Sainte Justine is that if the baby’s exam is close to qualifying, and we aren’t quite sure, then we usually cool them. Therapeutic hypothermia has a very favorable safety profile, sometimes PPHN gets worse, (and we once had to terminate cooling at 60 hours because the PPHN became uncontrollable and the only other option was ECMO).  Apart from that there are few complications unless the babies get too cold. Unfortunately babies with milder encephalopathy don’t like being cooled, they tend to seem uncomfortable, and often need some sedation which complicates their evaluation.

I think we need an RCT. I thought I would surprise you with that one! Infants with mild encephalopathy at 6 hours of age could randomized to be cooled or not, and stratified according to the aEEG patterns. Infants with mild encephalopathy before 6 hours could be reassessed at 6 hours to ensure they hadn’t progressed, and to avoid cooling babies who recover. They will then need to be followed quite a long time I think, the incidence of long-term problems is low enough that the sample size will have to be quite large.

I am still not sure that MRI findings are predictive enough of long-term outcomes that they could be used as a surrogate outcome (also known as a “biomarker”). I do think that if you found a positive effect of therapeutic hypothermia on MRI findings in mild HIE, that would probably justify more widespread cooling of mild encephalopathy; but if you found no MRI effect I think you would still need the clinical follow-up to be sure that there was no real benefit.

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It doesn’t make much difference how often we feed babies

Over the years there have a number of studies comparing two different feeding regimes. Most recently there has been a comparison of 2 hourly vs 3 hourly feeds and a comparison of feeds every 3 hours compared to 4 feeds an hour.

The first of these randomized 150 babies in 2 Malaysian NICUs who were 1 to 1.5 kg birth weight to either being fed every 2 hours or every 3 hours (Ibrahim NR, et al. Two-hourly versus 3-hourly feeding for very low birthweight infants: a randomised controlled trial. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2016). They were enrolled at the start of the feeds (average day 2) and the primary outcome was time to what they called “full enteral feeds” which was 100 mL/kg/d for 2 consecutive days. Which is quite a long way from full enteral feeds! Very few of the babies were getting breast milk (about 50%) feeds were increased by 15 to 20 mL/kg/d by protocol, but in fact it took 11 days (3 hour feed group) or 10 days (2 hour group) to reach 100 mL/kg/d. So in reality the increases were less than 10 mL/kg/d. There were no differences in any outcomes, neither the primary nor the secondaries, except for time to regain birth weight, which was slightly faster in the 3 hourly group.  But there were several secondary outcomes, so the reliability of this data is doubtful.

The second study (Rovekamp-Abels LW, et al. Intermittent Bolus or Semicontinuous Feeding for Preterm Infants? Journal of pediatric gastroenterology and nutrition. 2015;61(6):659-64.) randomized nearly 250 babies of less than 1750 g birth weight to be fed by bolus feeds or what they called semicontinuous feeding. The babies all received minimal enteral nutrition “trophic feeds” starting on day one, which were given every 4 hours of 0.5 to 2 ml depending on birth weight. The next day they started increasing feeds, at 24 mL/kg/d on day 2 up to 120 mL/kg/d on day 6 if there were no hold ups. Bolus feeds were given every 3 hours, using gravity over 15 minutes. The “semicontinuous” feeds were given in the same daily volume, so each mini-feed was 1/12 the volume of the 3 hourly feed, by gravity via an open syringe attached to the NG tube that was topped up every 15 minutes during the day. The primary outcome in this study was the time to full enteral feeding, which in this case was 120 mL/kg/d. Dutch NICUs back-transfer babies very quickly, often when the baby has reached 120 mL/kg/d (which is when this group stops TPN) so there was a practical reason for choosing that outcome.

There were no differences in any outcome. The time to full feeding was indeed about 6 days on average (in both groups), with a very few babies holding out, being difficult to feed and still not on full feeds by 28 days (about 10% of them).

If you add these data to what is out there in the literature, there is no evidence that how we feed babies, bolus q3h or q4h, or continuous or semi-continuous, nor any evidence that increasing faster or slower, affects any important clinical outcome. In particular there is no evidence of any impact on NEC. Even starving babies for a few days compared to giving them trophic feeds doesn’t make a difference to NEC, though it may harm gut function and slow down the progression of feeds when they are eventually introduced (even that is not consistent in the literature). The only indication I think for not feeding babies is if they are in shock and you are concerned about gut perfusion. Otherwise we should be feeding babies early, increasing feeds as quickly as they can be tolerated, giving them breast milk, and ensuring they get probiotics.

One of the things that is fun sometimes is to read about some of the other practices and outcomes of centers who are presenting a study, things that slip into the manuscript.

In the first study, for example, the authors reported the outcome of reflux needing anti-reflux treatment, the reflux was “defined as unexplained apnoea/bradycardia based on clinical judgement and requiring anti-reflux treatment” : but as there is no association between apnea and reflux, no way to clinically diagnose reflux unless the baby is vomiting, and no anti-reflux treatment that is effective short of surgery, I have absolutely no idea what this is all about (but it wasn’t different between groups).

In the second study the authors give saline enemas to all babies who don’t pass meconium before 24 hours and then repeat them daily until the baby is pooping at the correct frequency. There is, of course, absolutely no evidence base for this practice. The other thing I noted was that the incidence of sepsis was very high, over 30% of the group of babies, who were under 1750 g enrolled in this trial (mean gestation 28.5 weeks) had at least one episode of sepsis. In comparison, recent data from the CNN show that babies under 1500 grams had about a 15% incidence of sepsis. Which makes me wonder if the 2 things are related, shooting saline up the bum of a small premie every 24 hours might be a good way to encourage translocation of enteral bacteria. I certainly can’t think it’s a good idea.


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Doctors are cheap

I’m sure most of us don’t think that the little trinkets (pens and notepads and such) or a few slices of pizza that we might receive from a drug company affects what we prescribe for our patients.

We would be wrong. Drug companies buy lunches for doctors because they know they have an impact. New rules have reduced the number of expensive free vacations and similar high priced gifts that were, sadly, never offered to me, but lunches and other small gifts are still allowed in some jurisdictions. The authors of this study (DeJong C, et al. Pharmaceutical Industry-Sponsored Meals and Physician Prescribing Patterns for Medicare Beneficiaries. JAMA internal medicine. 2016;176(8):1114-10) were able to get data from a registry of gifts to doctors and medicaid prescribing patterns. They focused on 4 drugs that I never prescribe and I don’t know anything about, which were the most prescribed drugs in their class of medication.

Most of the gifts were meals under $20, doctors who received a single meal promoting the drug of interest had higher rates of prescribing rosuvastatin over other statins , nebivolol over other β-blockers, olmesartan over other ACE inhibitors and ARBs  and desvenlafaxine over other SSRIs and SNRIs. Receipt of additional meals and receipt of meals costing more than $20 were associated with higher relative prescribing rates.

I am sure that most of this is unconscious, its hard to think of a shared pizza as an effective bribe, but getting a lunch free a few times in a year makes you feel more kindly disposed to the makers of rosuvastatin than the makers of the other statin whose name you can’t remember and whose rep never bothered to even get you a coffee.

You can see this graphically here:


Someone told the authors to finish the abstract with the following sentence, “The findings represent an association, not a cause-and-effect relationship” which is of course an incorrect statement. An association is not necessarily a cause and effect relationship. But it may be. Sometimes an association is found because there really is a cause and effect relationship.

Doctors can afford to buy their own lunches. Our prescribing practices should not be influenced by anything other than the good of our patients.

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Antenatal Consultations before very preterm birth; what do parents want?

Gaucher N, et al. Personalized Antenatal Consultations for Preterm Labor: Responding to Mothers’ Expectations. The Journal of pediatrics. 2016.

Call me biased, but I think is a game-changer. (One of the authors is my wife and colleague, another is a friend and colleague in the NICU at Sainte-Justine, and the others are my friends and colleagues also… just so you know). (Also, just so you know, I was not involved in this study in any way, apart from knowing about the study going on; I did review the final manuscript for language issues and suggest a few changes in wording (all the authors are francophone but speak and write excellent English) but that is my only involvement in this).

What they did was to approach mothers (who might have had their partner with them) within 72 hours after an antenatal consultation from the neonatal team for threatened preterm delivery before 32 weeks. They asked them to fill in a questionnaire, which was intended to find out what the mothers’ expectations and satisfaction with the antenatal consultation were.

The questionnaire is presented in an appendix (in an English translation).

Why did they do the study? There are many guidelines which describe what information should be transferred to parents anticipating a preterm delivery. Most of them concentrate on what information should be transferred to the parents, sometimes with a list of all the horrible things that can happen to an extremely preterm baby that parents should be informed about. Is that what parents want from their antenatal consultation? Few studies have asked that question.

Unlike many studies in this domain, the sample size was substantial, 229 mothers completed the survey instrument, they were hospitalised in one of 3 participating university teaching hospitals in Québec.

A few highlights from the results:

The women surveyed wanted information about prematurity, but also information about their role in the NICU, about feeding strategies, visiting schedules, and so on.

The majority were satisfied with the consultation, but only 57% reported getting the right amount of information, 39% felt that they received too much information about prematurity. Most (89%) were reassured, although 23% were worried by the consultation which is more than 100%, so some were both. More than half felt better prepared for their role as mothers in the NICU (58%), and many (56%) wanted a follow up meeting with the neonatologist.

In open-ended questions,women explained why they wanted a follow-up consultation: (1) they felt too stressed during the initial consultation; (2) they felt unprepared to ask questions; or (3) they did not remember all the information provided.

You will see in the methods that we do not have a decision aid or printed information sheet that we routinely give out. Although some studies have reported that decision aids are useful, the main effect that has been shown in publications is that information transfer may be increased, for example, one decision aid was considered potentially useful because “women recalled more disabilities”.  In that study the long-term complications are grossly exaggerated (for a 23 week infant the sheet states “if the baby survives, 2 out of 3 may never be able to walk, talk, see, hear”); recalling more complications certainly does not mean that the parents are more likely to find the consultation useful, that it helps in decision-making, or that better decisions are taken for the babies, especially if the complications are exaggerated.

I think this study is a game-changer as I said, because we should surely be adjusting our approaches to the individual mother (and father) to fulfill their wishes for the consultation, and not just to have a decision about intensive care versus comfort care, which has been the focus of the position statements I mentioned. We should be trying to personalize the encounter in order to give them the amount of information they want (either to make the best decision, or to be adequately informed if there is no real decision to make). From the results of this study we should also be giving information about the local NICU practices, about the mother’s participation in feeding, and discuss how to be a parent of an NICU baby, and we should be providing an easy way for the family to get a follow up visit; improvements which could help us to better address the needs of our families. Whether the same results would be found elsewhere is unclear, but having worked in other parts of North America, I don’t think our parents are much different to parents in southern California or Alberta.

The article ends with this statement :

Current investigations mainly concentrate on optimizing and standardizing information transfer regarding prematurity outcomes, and women want personalized and individualized information. Future studies should investigate how parents want to receive this information. The actual format of the antenatal consultation might not be ideal for these information needs. It is possible that some parents may prefer an interactive Web site, a group meeting with other parents, or to meet ex-NICU parents.

Interesting ideas, but I don’t think those alternatives should be alternatives, rather additional resources for parents, an in-person meeting with the neonatal team would still, I think be essential, but perhaps not, it is something that could be studied prospectively.

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Theatrical Placebos in Neonatology

Acupuncture is nonsense. There I have said it. I’ll probably get at least a few comments for this post, but I’m not backing down. Acupuncture is based on pre-scientific ideas about how the body works, believing that some sort of vital energy flows along meridians in the body, and that sticking a needle into the skin at certain specific points can have distant effects, by letting out the Xi.

Xi is non-existent, meridians are non-existent and there are no acupuncture points, they just don’t exist.

This is all ridiculous, and people with a medical education should know better. Trials of acupuncture in adults have shown that it doesn’t matter where you put the needles, or even if you puncture the skin or not. The better controlled the trials are the less effect there is, and trials with really good sham procedures don’t show a difference between the sham procedure controls and the actually needled groups.

Any effect is simply a placebo effect, and the whole procedure with its  insertion of needles and fake explanations has been characterized as a “theatrical placebo”. For a sampling of deconstructions of acupuncture studies just search acupuncture on the blog “respectful insolence” which you can do by following this link .

Unfortunately there are many who have been taken in by the pseudoscience of this quackery, even in neonatology. A few trials have even been published, including those using electrical stimulators of non-existent acupuncture points, and a few where lights have been shone onto those same points.

The two most recent studies I glimpsed are examples of those 2 methods, Abbasoglu A, et al. Laser acupuncture before heel lancing for pain management in healthy term newborns: a randomised controlled trial. Acupuncture in medicine. 2015;33(6):445-50. 42 term babies having a heelstick were randomized to laser acupuncture or sucrose. The study found that sucrose was better than shining a light on the Yintang point (the non-existent acupuncture points, scattered along the non-existent meridians, all have names, this one is between the eyebrows and is also called EX2).

Mitchell AJ, et al. Does Noninvasive Electrical Stimulation of Acupuncture Points (NESAP) reduce heelstick pain in neonates? Acta Paediatrica. 2016. This study used different fake acupuncture points (ZuSanLi (ST36), SanYinJiao (SP6), KunLun(Bl60), and TaiXi (KI3) which are on the legs) and randomized babies undergoing heelstick to 4 groups, sucrose with “Sham NESAP”, NESAP plus water, NESAP with sucrose, and sham NESAP with water. They randomized 142 term infants who were undergoing a heelstick procedure and analyzed the videos of their faces for PIPP scoring. In the Sham NESAP groups the electrodes were placed adjacent to these fantasy acupuncture points but the stimulator was not turned on, All babies at least had facilitated tucking and a soother, which are both effective at reducing pain from heelstick, which was shown by the relatively small mean increases in PIPP scores in all the groups. Sucrose limited the increases in PIPP compared to the groups which didn’t get sucrose, and electrical stimulation of ZuSanLi etc didn’t do anything. This study did at least have the potential for a measurable effect, because, unlike shining a light on the skin, there is at least a potential that the transcutaneous electrical stimulation could have an analgesic effect. As it appears to for, in particular, chronic pain.

Although the NESAP groups without sucrose didn’t have a large mean increase in PIPP scores, the mean peak scores were up to 4.9 and 5 (compared to 4 or less for the sucrose groups), but the standard deviations of those scores were much larger than the sucrose groups, (4 compared to less than 2) which means that there were probably substantially larger numbers of babies who had pain scores of over 6, and had appreciable pain. Which means that yet again I can say that we shouldn’t be performing heelsticks without using all the proven evidence-based methods for reducing pain prior to such procedures, of which sucrose is top of the list.

Lets stop investigating this nonsense in neonatology, we should be using our time and efforts and resources to examine therapies that have some basis in reality and science. Whatever next, ear candling, or craniosacral therapy for newborns? OH NO!

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