Neonatal Research

Human breast milk is the best food for human babies. Although the evidence for some of the benefits is not as sound as I would like, I think it is clear that the benefits for preterm infants are substantial. Hence the growth in human milk banks, which are now supposed to be run according to standards which are similar to those for blood product banking (which makes the milk much more expensive than in the olden days). One possible risk of having such banks is that it might reduce the use of mothers own milk.

Two recent publications are reassuring; (Delfosse NM, Ward L, Lagomarcino AJ, Auer C, Smith C, Meinzen-Derr J, Valentine C, Schibler KR, Morrow AL: Donor human milk largely replaces formula-feeding of preterm infants in two urban hospitals. J Perinatol 2012.)  2 Hospitals in Cincinnati introduced a program to supply donor milk in 206, and progressively over the subsequent years, as donor milk increased, there was much less formula used, but no apparent effect on breast milk use.

The other is an observational study from a number of Italian NICUs, some of them had Human milk banks, and others did not; (Arslanoglu S, Moro GE, Bellu R, Turoli D, De Nisi G, Tonetto P, Bertino E: Presence of human milk bank is associated with elevated rate of exclusive breastfeeding in vlbw infants. J Perinat Med 2012:1-3). . Exclusive breastfeeding rate at discharge of very low birth weight infants was significantly higher in NICUs with a milk bank than in NICUs without (29.6% vs. 16.0%, respectively). Any breastfeeding at discharge was 60.4% vs. 52.8%, P=0.09. These are not very impressive rates, but they at least don’t suggest an adverse influence of having a breast milk bank.

I hope all my loyal fans (!) are not too disappointed by the lack of posts over the past few days, it was Newtonmas after all. Also, a couple of days after the celebration of the great man’s birthday, there was a record snow fall in Montreal, 45 cms in one day. This is what it looked like when I tried to get my car out to go to the chalet.

At least I had 3 loyal helpers

who shovelled with me, and then we all went to the chalet with very limited web access. We all went skiing for a couple of days; and now back to the grind, 69 babies in our 65 beds… oh well.

Happy New Year to everyone.

Making the milk thicker, in order to make it harder to reflux, has a long history in the treatment of GE reflux, or spitting-up babies. As I mentioned in a previous post there are some thickeners that have been associated with NEC, specifically xanthan gum.

In general, in good studies, the effects of thickeners have been modest or absent, in terms of reducing reflux. One group has previously studied Gaviscon, which is an alginate that sort of clots in the stomach, so reducing reflux. They showed that it did reduce reflux, but did not reduce apnea.

The most recent study from that same group looked at the effects of another agent, amylopectin. They again showed in a small cross-over RCT that thickening reduced reflux (in this case acid reflux but not non-acid reflux) but did not reduce apnea, the most parsimonious explanation for this is that reflux has nothing to do with apnea.

That is exactly the interpretation that Christian Poets puts on the data in his accompanying editorial .

In fact Corvaglia and colleagues are the only group that has consistently shown a relationship between reflux and apnea. If you look at their data closely, it appears that the apneas that they find after feeds more than between feeds, and that they seem to show are associated with reflux on Multi-luminal impedance monitoring, are short apneas of 5 seconds or more. It does not appear that pathologic apneas, with associated hypoxia and bradycardia are associated, even in their studies. Maybe this is the difference to other investigators, and the reason why those others, who only looked at longer, pathological apneas, have not found any association.

Yet another small RCT of probiotics. This time 150 infants less than 1500 grams birth weight in an NICU in Mexico were randomized to a mixture of 4 different Lactobacilli and Bifidobacterium infantis or control. There was a reduction in NEC stage 2 or greater (6/75 vs 12/75) of about the same magnitude as all the other trials. They also had lower mortality, and no adverse effects.

Here is the funnel plot with the new new study added. I can only say it again, its time we stopped doing placebo controlled RCTs and focused on finding the best preparation, and the optimal dose and timing. RCTs in women at risk of preterm delivery are also a good idea.

Abbas W, Attia NI, Hassanein SM: Two-stage single-volume exchange transfusion in severe hemolytic disease of the newborn. The journal of maternal-fetal & neonatal medicine. 2012, 25(7):1080-1083. In this randomized clinical trial the authors did 104 exchange transfusions, they randomized the infants to either have a standard double volume exchange or the experimental technique which was to wait for 3 hours between the 2 single volume exchanges. The immediate effects were identical with a good lowering of the bilirubin, but the intervention group had much less rebound after the exchange was finished, to about 210 rather than 290. Unfortunately the report doesn’t clearly state when the rebound levels were taken, or even if they were measured at the same time in each group, but it looks like they were taken at 3 hours post exchange according to one of the tables. Also fewer of the intervention group needed as 2nd exchange.

In my hospital to do a study with 104 exchanges would take about 104 years, which means 2 things to me, 1. to improve techniques and treatments for severe jaundice we have to rely on studies from countries without well established anti-rhesus IgG programs. 2. Those countries need to develop anti-rhesus IgG programs!

Berry J, Griffiths M, Westcott C: A double-blind, randomized, controlled trial of tongue-tie division and its immediate effect on breastfeeding. Breastfeed Med 2012, 7(3):189-193. This is one of the oldest debates in care of the newborn, does tongue-tie affect feeding, and does cutting the tie improve feeding. This was an RCT in breastfed babies. The observer scoring the rbeastfeeding adn the mother were masked as to whether an actual frenulotomy had been performed or not, the baby was taken away from the mother, either a real or sham frenulotomy was performed and the babe was then returned to the mother with a piece of gauze under the tongue. There were 30 babies in each group, and the primary outcome was improvement in breast feeding. The tongue tie group had 78% of the babies feeding improved after the procedure and the controls 48%.

there are a couple of issues with this study, 1 I don’t know if you should really call this double blind as the baby probably knew it had the procedure! and 2. seriously this time, there was no anesthetic or analgesic used. I think that is appalling. there is no reason why a little topical anesthetic or at least some analgesia, such as sucrose, could not be given. The authors state that there is a NICE guidance, which they say requested further studies to provide evidence ‘that division of tongue-tie without an anesthetic in infants is safe,  successful, and acceptable to parents’. In fact the guidance requests no such thing. The NICE review notes that the procedure is usually performed without anesthesia, and suggests further studies, but does not suggest further studies without anesthesia, it is in fact silent on the issue as far as a recommendation is performed. Also the study was actually performed in 2003 and 2004, so they can’t use the NICE guidance published in 2005 as justification for not giving analgesia. Some infants do sleep through the procedure, but others cry and do demonstrate pain responses.

It certainly now looks like division of a tongue tie improves poor breast feeding, as well as reducing nipple pain ( as shown previously) so a referral to someone who has been trained to do it seems appropriate, but find someone who gives an anesthetic, or at least some analgesic.

Autrata R, Krejcirova I, Senkova K, Holousova M, Dolezel Z, Borek I: Intravitreal pegaptanib combined with diode laser therapy for stage 3+ retinopathy of prematurity in zone i and posterior zone ii. European journal of ophthalmology 2012, 22(5):687-694. This multi-center RCT of retinopathy treatment enrolled a very high risk group of babies. Stage 3 with plus in zone 1 or poterior zone 2. They compared laser plus pegaptanib, a VEGF-165 inhibitor. Apparently this agent is more selective than the one that was used in the BEAT-ROP trial (called bevacizumab) it is an RNA aptamer whatever that means! The biggest other difference between this trial and BEAT-ROP is that all the babies in both groups got laser therapy. The conventional treatment group received laser therapy ‘combined with cryotherapy’ but the cryo is never described, we don’t know who got cryo for what indications. The authors state that they followed the ETROP recommendations, but those recommendations don’t suggest combined laser and cryotherapy, so I don’t undestand this at all.

One of the major advantages of anti-VEGF treatment as far as I can see is avoidance of laser. Laser therapy injures the peripheral retina, requires a very sedated baby, often one who has to be re-intubated for the procedure, and as many of the babies also have BPD, avoiding re-intubation is a big advantage. The primary outcome of this trial was recurrence of stage 3+ disease, and there was significantly less recurrence after pegaptanib than after conventional therapy, 15% versus 50%.

Pasquali SK, Ohye RG, Lu M, Kaltman J, Caldarone CA, Pizarro C, Dunbar-Masterson C, Gaynor JW, Jacobs JP, Kaza AK et al: Variation in perioperative care across centers for infants undergoing the norwood procedure. J Thorac Cardiovasc Surg 2012, 144(4):915-921.
Ohye RG, Schonbeck JV, Eghtesady P, Laussen PC, Pizarro C, Shrader P, Frank DU, Graham EM, Hill KD, Jacobs JP et al: Cause, timing, and location of death in the single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):907-914.
Tabbutt S, Ghanayem N, Ravishankar C, Sleeper LA, Cooper DS, Frank DU, Lu M, Pizarro C, Frommelt P, Goldberg CS et al: Risk factors for hospital morbidity and mortality after the norwood procedure: A report from the pediatric heart network single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):882-895.
Ghanayem NS, Allen KR, Tabbutt S, Atz AM, Clabby ML, Cooper DS, Eghtesady P, Frommelt PC, Gruber PJ, Hill KD et al: Interstage mortality after the norwood procedure: Results of the multicenter single ventricle reconstruction trial. J Thorac Cardiovasc Surg 2012, 144(4):896-906.
These publications are all from the Single Ventricle Reconstruction Trial, which was a surgical RCT of about 550 infants with hypoplastic left heart syndrome randomized to different forms of the Norwood procedure. These secondary analyses show that there are enormous variations in many different aspects of perioperative care, and that many babies die between different stages of the surgical repair. Bravo to the collaborators for doing a very difficult trial. The next stage will be to do more trials to find out which of these differences in care really have an impact on clinical outcomes.