Reducing severe IVH/PVL through exclusive human milk diets. Is this the real thing?

Reducing severe IVH/PVL through exclusive human milk diets. Is this the real thing?

Anyone who works in the NICU is more than familiar with the sad moment when you find out an infant has suffered a severe IVH (either grade III or IV) and the disclosure to the family. The family is in a state of shock with the fear of ventricular drainage a reality that will likely come to pass.  We have spent many years trying to find ways to reduce this risk and antenatal steroids and delayed cord clamping are two relatively recent interventions that have had a real impact.  Unfortunately we have not been able to eliminate this problem though.  What if something as simple as an exclusive human milk diet could be that magic bullet to further reduce this problem in our NICUs?

Exclusive human milk diets

I have written about this topic before but as a refresher this generally refers to all sources of nutrition being derived from human milk.  Ideally we would provide mothers own milk (MOM) but when this is not available units rely on pasteurized donor human milk (PDHM) as the base feed.  Added to this is human derived human milk fortifier (H2HMF) as opposed to bovine powdered or liquid fortifier usually to provide a base caloric density of 24 cal/oz.  

Reducing IVH Through Exclusive Human Milk Diets

It would be nice to have a prospective multicentre trial with this as the outcome but there is a significant problem when doing this type of study.  The H2HMF is costly with a price tag of about $13-15000 per treatment course so to do a prospective RCT would not be easy for units that don’t use the product already.  Moreover, for those units that are already sold on the product it would seem unethical if there was no equipoise to randomize to bovine or human fortifier.  As such, when we talk about getting the best evidence it is most likely going to come in the form of a retrospective study as has been done here by Carome K et al in their paper Exclusive human milk diet reduces incidence of severe intraventricular hemorrhage in extremely low birth weight infants.

The authors in this study chose to look at three different time periods with different approaches to feeding of ELBW infants. They were as follows with all diets providing H2HMF going until 34 weeks. Aside from the source of nutrition, starting of and incremental advancement of feedings was protocolized as per unit approach.

2012 to 2014 – MOM was given when available. Preterm formula was the alternative as a supplement Fortification of was with bovine milk-derived liquid fortifier
2014 to 2015 – H2HMF used in those infants receiving exclusively MOM. All others received preterm formula as supplement or alternative. If MOM was available but in insufficient quantities for sole diet, it was fortified with bovine-HMF
2015 to 2017 – all ELBW infants received an EHM diet consisting of MOM if available and PDHM as a supplement to MOM or as full diet, each fortified with H2HMF

The maternal demographics were similar between those receiving exclusive human milk diets and those without except for a higher antenatal steroid provision in the EHM group. This of course bears consideration in the results as steroids have been shown to reduce IVH.

Looking at the results below shows some very promising findings. The incidence of Grade III/IV IVH and/or PVL was 7% in the EHM group and 18% in the non-EHM group. Also noted to be quite different was the incidence of NEC which was 5% in the EHM and 17% in the non group. The authors also did a subgroup analysis looking at the use of MOM vs PDHM and found no difference in outcomes regardless of source of human milk used. As the authors point out this might mean that the pasteurization process does not denature the components of milk responsible for these protective effects if the results are to be believed.

One strength of the study was that the authors performed a logistic regression to control for the higher rate of antenatal steroid use and lower rates of NEC in the EHM group since both would be expected to influence rates of IVH/PVL and found that the results remained significant after this analysis. The findings were an OR of 2.7 CI 1.2–6.0, p = 0.012 so that is promising!

What They Weren’t Able to Do

It’s possible I missed it in the article but like several other papers on this topic the babies who received formula and those who received human milk with bovine fortifier were grouped together. As such what we don’t know from this study is whether the addition of just the bovine fortifier vs H2HMF would have yielded the same results.

Nonetheless what the article does suggest is that use of EHM diets are protective against severe IVH/PVL regardless of the source of human milk when you compare it to receipt of any bovine sources. The caveats about retrospective studies of course exist as per usual but if this is the best evidence we have how do we use it? At the very least this calls out for strategies to maximize milk production for mothers and to use PDHM when MOM is not available. It certainly is suggestive that the use of H2HMF may confer benefit as well. What you unit does with this information I suppose will need to be determined based on the totality of the evidence. I suspect there is more of this story to be told and this adds yet another chapter in the tale of EHM.

Seizure control.  Tried and true or the new kid on the block?

Seizure control. Tried and true or the new kid on the block?

Phenobarbital at least where I work has been first line treatment for seizure control for as long as I can recall. We dabbled with using phenytoin and fos-phenytoin in the past but the go to tried and true has been phenobarbital for some time. The use of this drug though has not been without trepidation. Animal studies have linked phenobarbital to increases rates of cerebral apoptosis. Additionally, in a retrospective comparison of outcomes between seizures controlled with phenobarbital vs Levetiracetam, the latter came out ahead in terms of better long term developmental outcomes. This study from 2013 was entitled Adverse neurodevelopmental outcomes after exposure to phenobarbital and levetiracetam for the treatment of neonatal seizures. Purists of course would argue the need for a prospective trial and that is what we have to chat about here.

Levetiracetam vs Phenobarbital

The study in question was a multicenter randomized phase IIb trial (searches for a dose that provides biological activity with the minimal side effect profile) that compared two doses 40 mg/kg and 60 mg/kg of Levetiracetam with standard doses of phenobarbital. The study was done by Sharpe C et al and called Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial.

In this study patients were randomized to receive levetiracetam or control phenobarbital treatment group in a 60:40 allocation ratio by using a block randomization strategy and stratified by site. The trial design is shown in the diagram below.

The study was designed to not delay institution of the accepted treatement with phenobarbital as usual first line treatment of seizures by more than 1 hour. The strength of this study was that the authors used electrographic seizures confirmed by continuous EEG monitoring. The efficacy of medication effect was blindly interpretted by two independent electrophysiologists. in other words the authors went out of their way to ensure these were real seizures and moreover that any changes to medications were decided upon after interpretation of effect by people remote from the study. The primary outcome though in comparison to the aforementioned retrospective study was a short one. In this study the primary outcome was initialy absense of seizures for 48 hours but then was changed part way through the study to 24 hours. The change was a practical one since it was noted after data collection that in many cases EEG monitoring had been stopped prior to 48 hours.

The Results

Honestly it is the results that led me to want to talk about this study. They are the exact opposite of what i thought they would be. Based on my own experience with Levitiracetam seeming like a wonder drug when it comes to seizure control I expected the results to favour it. Not the case.

To say that phenobarbital crushed the competition is an udnerstatement. Having said that the incidence of side effects were higher with phenobarbital as well. Hypotension, respiratory suppression, sedation, and requirement for pressor support, were more common. Nonetheless, this study also included patients with HIE and found even in this subgroup phenobarbital was superior. This is important information as one could speculate that earlier seizure cessation in those with anoxic injury already could be especially beneficial.

What do we do with these results?

As the authors point out this is a study of short term outcomes. In the trial about long term outcome it was clear that treatment with phenobarbital leads to worse outcome than with levitiracetam. Having said that it was a retrospective study so the next step will be to conduct long term outcome studies to see effects. This presents the possibility of an interesting conundrum. What if the newer drug is inferior to tried and true phenobarbital at controlling seizures but leads to better long term outcome? Would you consider allowing seizures to persist longer than you might otherwise want to in the short term but then be able to reassure families that the long term outlook is bettter? The side effect profile of levitiracetam is such that I think neurologists want to use it but the other possibility is that there is another newer anticonvulsant that will need to be tested as wouldn’t it be great not to have to choose either poor acute seizure control but better long term outcome vs better seizure control with concerning long term outcome? As a parent I have no doubt watching a child eize would be terrifying and you would want it to end as soon as possible but the question with phenobarbital is at what cost?