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.
Skin to skin care (STS) or kangaroo care (KC) has quickly become one of the hot topics in neonatal care these days. The benefits have been spoken of before and as we learn more about the benefits it isn’t surprising to see studies emerge looking at novel groups who might benefit from the same. Dr. Kribs and her team in Cologne, Germany put themselves on the map with studies demonstrating the potential use of and benefits from LISA techniques for surfactant administration. The same unit is at it again but this time asking a different but very important series of questions.
Combatting the challenges the mother-infant dyad face after delivery
Traditionally, our smallest infants are resuscitated and shown to the parents before being taken to the NICU for ongoing care in an isolette. Dr. Kribs and her group wondered about the effect that separation could have on the mother-child interaction (MCI). The groups were comprised of infants born between 25 +0 – 32+ 0 weeks gestation. They postulated in a randomized controlled trial that after stabilization with or without surfactant that there would be a benefit to having these dyads spend 45 minutes in STS vs the traditional 5 minute visual contact with touching allowed of the face but not anywhere on the body since the infant was wrapped in protective thermal wrap. To test the difference in MCI at 6 months the authors shot a 4 minute video of the mother and child together and using blinded reviewers assessed the interaction between the dyad. The interaction involved the mother changing the diaper and playing with their children.
From the study; “Maternal and infant behavior was assessed using the Mannheim Rating System, a well validated standardized observation instrument(16). Videos were analyzed by two trained raters blind to randomization.”
Self reports of other important outcomes such as depression, bonding and more objective study of salivary cortisol were also performed. Salivary cortisol elevations were apparently blunted in another study at 4 months of age in infants who experienced more pain and stress in the NICU.
The studies title is Delivery room skin-to-skin contact for preterm infants – a randomized clinical trial
What did they find?
Like many studies looking at a brief intervention in the life of a child this one had some findings that are worth discussing.
Overall, the rate of positive MCI was higher in the group randomized to STS (86 (±26) vs 71 (±32), p=0.041, OR 0.982, CI [0.7-1]). This difference was due to three particular differences in the MCI studies.
Maternal motoric response, infant vocal response and infant motoric response. What this meant specifically is that infant and maternal physical interactions were deemed positive in terms of facial expressions, physical movement or vocalizations more when delivery room STS was performed than when not. Infants were also more vocal with their mothers when they had experienced this intervention.
Also on the 3rd day of life maternal depressive symptoms were higher in the group randomized to only see their infant for 5 minutes. This was in spite of controlling for factors expected to confound the result. Salivary cortisol did not show a difference at 4 months. While the study was underpowered for the secondary outcomes there was no increase rate of IVH or other adverse outcomes in the study so take that for what its worth.
Lastly, there was less hypothermia in the group randomized to STS care on admission.
Some lessons from this study
As the authors note it is possible that parents prepped themselves for the videos but the number of parents that “put on a show” should roughly be equal between the groups. Not sure given the low number of patients in the study if that would have truly balanced out but the results to me seem plausible. Having a preterm infant for most families who really don’t know what to expect can be a terrifying experience. Such parents may develop the vulnerable child syndrome in which parents hover over their children feeling as if they need to be over protective given the perceived frailty of the child. This constant worry can lead to stress for the family and affect the parent-child interaction. What if you were able to hold your baby though almost from the start for 45 minutes against your chest and see that your infant wasn’t as fragile as you might have thought? Could this lead to a reduction in depressive symptoms by 3 days as found here? Might you spend a lot more time in kangaroo care as the journey of the patient continues in the NICU?
These were not all healthy babies as about 80% in both arms received the LISA procedure for administration of surfactant and then went on to CPAP. To most parents these babies would have indeed appeared fragile but perhaps showing the families that the babies were stronger than they looked and moreover allowing the families to not just be observers but provide direct care indeed had an impact on their mood and that carried over to childhood.
No doubt the naysayers out there will want a larger study that looks at other outcomes in terms of harm such as IVH and sepsis but this study certainly shows the strategy is possible and may just have enough benefit to make it standard of care some day.