I presented this topic as a fellow many years ago after a paper came on the scene suggesting better outcomes with a faster approach. The paper Randomized trial of “slow” versus “fast” feed advancements on the incidence of necrotizing enterocolitis in very low birth weight infants. was plagued by the same issue as others created around those years which was a small number of patients at the lowest gestational ages. Any differences in sub analyses were difficult to really believe as the outcomes could have easily been explained by chance. Having said that, many centres began advancing feeds a little faster than the typical 20 ml/kg/d in favour of 30 ml/kg/d. It would take some time to coordinate a trial large enough to really answer questions about relevant issues such as time to developmental outcomes, time to full feedings and rates of NEC and the time appears to be now.
The SIFT trial
This trial was the result of a great deal of coordination between 55 different centres. For inclusion, infants had to be <1500g and <32 weeks gestational age at birth. Once the decision was made to advance feeds, babies were randomized to receive increases of 18 mL/kg/d vs 30 ml/kg/d. The primary outcome was survival without mod-erate or severe neurodevelopmental disability at 24 months CGA. What is striking about the study is its size. The number of babies in the fast arm was 1394 while 1399 in the slower group. In terms of having sufficient numbers of infants who were at the earliest gestational ages they were able to accomplish this as shown in this table.
Importantly when looking at the primary outcome 87.4% of infants in the faster group vs 88.7% in the slower group were followed up for assessment. It is also worth mentioning that this is even more impressive in terms of retention when one considers that about 6% in both arms died before assessment.
What were the findings then?
There was no difference in the primary outcome or for that matter each of its’ competing parts.
The authors in a secondary analysis did show a very marginal significant finding favouring slow feeds with respect to motor outcome. I concur with the authors though that given the small effect size and the “fishing” for results this likely is simply a chance finding. I can’t think of any reason why that would be the case either from a biological standpoint.
Not surprisingly another significant finding was shorter durations to reach full feeds (10 vs 7 days) and days on TPN at 11 vs 9 in the slow vs fast groups. In spite of having less need for central venous access, the authors were unable to show a reductoin in late onset sepsis or NEC.
Does it change your management?
I suppose that depends on what your management currently is. If you are like our centre and already advancing feedings by 30 ml/kg/d then I suspect not much. If you are in a slow centre one can take away from this study that at the very least you can lessen your patient’s need for central venous access and TPN. Based on this study and my suspicion that there will be no bigger trial forthcoming, whatever you decide to do this is about the best data that you will be getting.
My co-author Dr. Seth Marks from Pediatric Endocrinology spent countless hours reviewing the evidence and fielding seemingly endless questions from reviewers and myself. The support from the CPS was also much appreciated as the back and forth from so many who expressed opinions would have been difficult to manage without their support. What I hope you will find as you read this is the best appraisal of the evidence and directions for care that we could come to in 2019. Where things will stand by the time we make it to the next revision will be interesting to see.
For those who have used the Acute Care of At Risk Newborns (ACORN) program you will be pleased to know that the upcoming new version of this program is completely alligned with the approach outlined in the CPS statement. Given that the first version of ACORN and the CPS were not aligned and caused great discussion and distress at times, we feel this is a big accomplishment.
The algorithm for managing hypoglycemia is clean and easy to follow (I think) and we hope such clarity will greatly help with managing those infants at risk.
Main Questions for the Future
We remain a country divided (much like the recent election) with respect to dextrose gels usage. There are centres which are leary of using adult formulations of dextrose gel in newborns whereas others have adopted such treatments with success. The algorithm and statement address the approach to using dextrose gels or what to do if one wishes to avoid such use. With time, local products or a national brand designed specifically for newborn use may come to be and this will need to be addressed at some point.
Changing the threshold at 72 hours and beyond to require glucose levels of greater than or equal to 3.3 mmol/L may lead some to be worried about a ramp up in admissions but at least locally we have not seen this. In the end those with persistent causes of hypoglycemia will manifest one way or the other and whether it is before or after discharge from the hospital may be a reflection of what threshold you feel comfortable using.
Will local guidelines be affected by adopting the changes outlined in this statement? I suspect so and would welcome feedback before the next version of this document is worked on to determine what if any ramifications (positve or negative) such approaches have had.
No doubt with many changes compared to the previous version of the statement there may be some surprises. Keep an open mind and look at the evidence presented. In other cases the lack of evidence has motivated a change in position. Either way we believe this is the best approach to care for at risk newborns given what we know today.
Any regular reader of this blog will know that human milk and the benefits derived from its consumption is a frequent topic covered. As the evidence continues to mount it is becoming fairly clear that the greater the consumption of mother’s own milk the better the outcomes appear to be with respect to risks of late onset sepsis or BPD as examples. Moving to an exclusive human milk diet has been advocated by some as being the next step in improving outcomes further. While evidence continues to come suggesting that replacement of fortification with a human based instead of a bovine based fortifier may improve outcomes, the largest studies have been retrospective in nature and therefore prone to the usual error that such papers may have.
What is evident though as the science pursues this topic further is that the risk of necrotizing enterocolitis or NEC is not zero even with a human milk diet. Why is that? It might be that some risks for NEC such as intestinal ischemia or extreme prematurity simply are too much to overcome the protective effect of breastmilk. Perhaps though it could be related to something intrinsic in the breastmilk that differs from one mother to another with some producing more protective milk than others.
Secretors vs Non-secretors
When it comes to the constituents of breastmilk, human milk oligosaccharides or HMOs are known to be secreted into breastmilk differently depending on whether a mother has a secretor gene or not. this has been demonstrated recently in HMOs affecting the microbiome in infants Association of Maternal Secretor Status and Human Milk Oligosaccharides With Milk Microbiota: An Observational Pilot Study. HMOs are capable of a few things such as stimulating growth of beneficial microbes and acting as “receptor decoys” for pathogenic bacteria. Previous rat models have also demonstrated their potential to reduce NEC in rat models. Essentially, mothers who have the secretor gene produce more diverse types of HMOs than mothers who are secretor negative.
What came out of the study were a couple very interesting findings. The first is that when analyzing the HMOs present in breastmilk at 2 weeks and comparing those who developed NEC to those who did not there was one significant difference. Lacto-N-difucohexaose I (LNDH I)had a median level of 0 (IQR 0-213) from the milk of those mothers who had infants affected by NEC. There were no differences observed for any other HMOs.
Also of interest was the greater diversity of HMOs present in the breastmilk samples of mothers whose infants did not develop NEC. This was present at all time points.
How Could This Be Useful?
If a broader array of HMOs is associated with less risk of NEC and the presence of LNDH I carries the same association it opens the door to the next phase of this research. Could provision of LNDH I in particular but moreover a wide array of HMOs to mother’s milk reduce the occurrence of NEC? This will need to be tested of course in well designed randomized trials but this type of fortification could be the next step in what we add to human milk to enhance infant outcomes. Given that it may be difficult to determine in short order whether women have these HMOs already a broad based fortification strategy assuming insufficient amounts of HMOs would be best. A quick search on clinicaltrials.gov shows that there are 101 trials in children looking at HMOs at the moment so more information on this topic is certainly on the way. Could HMOs be the magic bullet to help reduce NEC? Just maybe!
The Ortolani and Barlow manouvers are probably the two most requested parts of the physical exam that students ask to be shown. We line up several medical students who take turns applying the steps of abduction and then adduction, testing the stability of the hips. We routinely give oral sucrose, position in kangaroo care or breastfeed while performing other noxious stimuli such as heel lancing but at least in my centre give nothing for manipulating the hips in such a fashion.
So the authors set out to compare findings in these 28 infants and standardized the study as much as they could by having one Neonatologist perform all hip exams and having a video recording of the infant’s face during the procedure assessed by two independent reviewers in order to assign the PIPP-R scores. While not a randomized trial, for the type of intervention being studied this was the right approach to take to determine the answer to their question.
Interesting findings indeed. Statistically significant differences were noted in bilateral changes in oxygen extraction during hip examination as well as for the GSR small peaks. The PIPP-R scores as well were vastly different between the two groups suggesting that the areas of the brain responsible for perception of pain were indeed activated more so with manipulation of the hip than with auscultation of the heart.
What can we take from this?
The hip exam may elicit responses indicating pain but there remains the question of how much is actually elicited. Nonetheless, the authors findings are intriguing as they certainly challenge the notion that this is a quick exam that should be just done and gotten over with. Clearly bundling or Kangaroo Care are not an option here due to the nature of what is being done. The next time you are planning on doing such tests though should you at least consider non-nutritive sucking on a pacifier or sucrose solution if readily available? If not readily available then should it be?
Oral immune therapy (OIT) has really taken off at least in our units. The notion here is that provision of small amounts (0.2 mL intrabucally q2or 24 hours) can prime the immune system. Lymphoid tissue present in the oropharynx and intestine exposed to this liquid gold in theory will give the immune system a boost and increase levels of IgA. Such rises in IgA could help improve the mucosal defence barrier and therefore lessen the incidence of late onset sepsis. Rodriguez et al described this in their paper Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives in 2009. They followed it up the next year with a pilot study demonstrating how to actually administer such therapy. The fact that this approach has been adopted so quickly I think speaks to the principle that this kind of therapy falls into the category of “can’t hurt and might help”. The real question though is does it actually make a difference?
Recently, authors from Brazil presented their findings from a single centre double blind RCT entitled Randomized Controlled Trial of Oropharyngeal Colostrum Administration in Very-low-birth-weight Preterm Infants. This authors are commended for studying this practice in such a fashion and included infants <34 weeks who were <1500g at birth to receive the above mentioned intervention. These infants were compared to placebo who received the same intervention except instead of mother’s own colostrum they were given sterile water. In total there were 149 infants randomized with 81 receiving OIT vs 68 who received a placebo. The primary outcome of interest on which a power calculation was performed was the incidence of late onset sepsis. Other typical outcomes including NEC, ROP, BPD, IVH and death were also followed.
Did they find a difference?
Sadly to many of you I am sure they did not as is shown in the table below.
Surprisingly the authors also looked at levels of IgA in infants in both arms and also found no difference.
There is a big problem with this study however that no doubt will lead to a repeat version at some point. While the authors enrolled the numbers above, the numbers that were analyzed in the table are 34 lower in the OIT arm and only 2 lower in the placebo group. In essence, a large number of mothers after enrollment were not able to provide the colostrum that was needed for the study. The study called for 48 applications over a 48 hour period and a little more than half of the mothers were able to do it.
Do not be dismayed then that no difference was found here. There is no need to “throw the baby out with the bathwater” and abandon OIT based on this one study. I think what is needed in the future though is a study that enrolls far more than needed to account for attrition due to loss of mothers who can complete the study. Without another study I think the practice will continue but does it really make a difference to rates of sepsis? Who knows but there is no doubt it helps parents who are feeling that they have lost control of a pregnancy that has gone wrong, a positive experience and the feeling that they are doing something for their child.