Improving Nutrition in the very Preterm; more protein?

A new study published in Pediatrics looked at the question in the title of this post. Moya F, Sisk PM, Walsh KR, Berseth CL: A new liquid human milk fortifier and linear growth in preterm infants. Pediatrics 2012.  This was a modestly sized trial (n=140) comparing 2 human milk fortifiers from Mead-Johnson, one which may be their standard commercially available powdered one (it isn’t clearly stated), the other a new highly concentrated liquid fortifier. There are a number of problems with this study. 1. It was funded by Mead Johnson, and there is no statement as to who controls the data, nor whether the 2 authors who were not Mead-Johnson employees saw or analysed the raw data. 2. It is said to be a multicenter trial, but the number of centers and their identity are not revealed. 3. The concentration of the new liquid fortifier is not described, we are only told that 5 vials of fortifier were added to 100 mL of breast milk, but does that make 50 mL or 0.5 mL? Diluting the good stuff in breast milk as little as possible is why we mostly switched to powdered fortifiers, so we need to know! 4. A table in the publication is stated in the text to show the composition of the fortifiers, but actually shows estimated composition of preterm human milk plus fortifier, and they do not give a reference to where they chose the data about preterm human milk composition. 5. The power calculation is for 50 patients per group, but they enrolled 150 infants. 6. Neither of the 2 analyses performed were truly intention to treat, the first analysis excluded the 4 randomized infants who never got the fortifier (they call this “similar to intention to treat”), the second excluded more than half of the babies in each group according to how much fortifier they received. Even for the first of these analyses they excluded 17 controls and 23 liquid fortifier patients before the end of the study when they discontinued the fortifier, so the final weight gain and growth variables presented only refer to a selected sub-group of 58 and 51 infants for the first analysis and 32 and 24 infants for the second analysis. 7. Finally there was no difference in the primary outcome. The primary outcome was weight gain in g/kg/d over the 28 days of the study, and none of the analyses of this were different. This is therefore a negative trial. However the last sentence of the abstract, which is all many people will read, states “Benefits of LHMF include improvements in growth”. Not as shown here they don’t. The only thing that was significantly different according to the slightly less unreasonable analysis #1 was that, after 28 days, the 2/3 of the enrolled infants remaining in the analysis who got the liquid fortifier weighed 100 g more, and were 0.9 cm longer. One big problem with this data is that we don’t know whether this sub-sub-group had the same weights and head circumference in the 2 groups at the start of the study. The only baseline data are given for the groups as a whole, not for those who had an analysis of the primary outcomes. As there were so many babies who dropped out of the study before the primary outcome was measured we should at least be told what were the baseline measurements of the 2/3 who remained.

Now I actually think this was probably a good idea, to make a fortifier which ends up supplying more protein, which, I didn’t mention above, was the main difference in the final composition of the milk plus fortifier (3.2g/100mL compared to 2.6g/100mL) there were a few other minor differences (including 3 kcal/100ml more energy with the new stuff). I am not sure if a liquid is better than a powder or not. But I think Pediatrics has really made some poor decisions about publishing this in this form, we need to know the final weight, length, and head circumference of all the randomized babies, or at the very least all of those who started on the study intervention, and it should be clear in teh abstract that this was a negative study.

A much more important issue for future studies is data on body composition. We know that very preterm babies, if you use ‘optimal’ nutrition to avoid postnatal growth restriction, still end up short and fat; so we need to improve what we consider optimal nutrition, with the initial goal that preterm babies when they reach term should have the same body composition as a full term baby that is a few days old, and the eventual goal that long term metabolic and other outcomes should be equivalent. Now my reading of the recent literature is that to do this we need to give more protein, at least during the enteral nutrition stage of the babies’ stay, and particularly among breast fed babies. The evidence to support that reading is here and here and here.

One recent study that may have worried a few people is by Cynthia Blanco and colleagues. This very small study which was designed to look at short term effects of earlier, higher protein administration during TPN. Babies were randomized to 2 amino acid advancement regimes that were only different during the first 7 days of life, the 1st group got 0.5 g/kg/d on day 1 increasing to a max of 3, and the 2nd group received 2 g/kg/day increasing to 4. After day 7 everyone received 3.5 g/kg/d. The authors added follow up to the study, but were only able to examine 32 of the 51 surviving infants at 18 to 24 months.

Now some problems with this study are that their babies are normally seen at 0,3,6,12,18 months corrected age, and 24 months chronologic age. Results are reported at 18 to 24 months and it is not at all clear how many babies were seen at each of those 2 ages. In addition the statistics do not seem to have been adjusted for multiple comparisons, so the finding that prompted an editorial in the journal, that the Bayley MDI was a little lower (11 points different, p<0.03) in the high AA group at 18 months, is almost certainly not significant if the large number of comparisons is taken into account. In addition, the difference disappeared at 24 months! So although the interesting initial metabolic and balance studies in this RCT are of interest, I don’t think there is any evidence here of a harmful effect of the higher intravenous protein load in the first week of these very preterm babies.

What is the optimal and the maximal protein intake remains uncertain.

About Keith Barrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
This entry was posted in Neonatal Research and tagged , . Bookmark the permalink.

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