Breast milk fortifiers, a new systematic review

A systematic review has just been published which compares the outcomes of milk fortification with bovine-milk derived fortifier and human-milk derived fortifier. (Grace E, et al. Safety and efficacy of human milk-based fortifier in enterally fed preterm and/or low birthweight infants: a systematic review and meta-analysis. Archives of Disease in Childhood – Fetal and Neonatal Edition. 2020:fetalneonatal-2020-319406)

The main conclusion is that the evidence is very weak, but I think that even that exaggerates the quality of the evidence! The extensive literature search, using terms designed to select randomized trials in which one group received bovine-milk derived fortifier (BMDF) and the other received human-milk based fortifier (HMDF), led to the inclusion of two trials with a total of only 332 infants. Unfortunately, those 2 trials studied different interventions, and in my mind should not have been meta-analysed.

We already know from published data, that using artificial formula, rather than pasteurized donor human breast milk increases Necrotising Enterocolitis. That is so whether the formula was used as a supplement to insufficient maternal breast milk, or as an alternative for babies not receiving maternal milk. Here is the relevant figure from the Cochrane review (Quigley M, et al. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2019;7:Cd002971) for the outcome NEC.

(I have mentioned before that if you want to access the Neonatal Cochrane Reviews full text free of charge you can do so via this Vermont Oxford Network page; if you find the review you are interested in and click on the link then the Cochrane library page somehow knows that Vermont sent you, and VON support universal access to the neonatal reviews.)

So given that we already know this with a moderate degree of certainty, any study which tries to determine the importance of the type of fortifier on NEC, or other outcomes, should compare only the fortifier, and ensure that the milk received was human milk (maternal or donor).

But one of the 2 trials included in the new SR was Sullivan S, et al. An Exclusively Human Milk-Based Diet Is Associated with a Lower Rate of Necrotizing Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products. The Journal of Pediatrics. 2010;156(4):562-7.e1. In that trial, there were 3 groups, one of which received artificial fortifier as the supplement to breast milk and BMDF, the two groups who received HMDF also received donor human milk as the supplement to mother’s own milk. So it was not a trial of human-milk derived fortifier alone, but a trial of HMDF and donor breast milk supplements, compared to BMDF and artificial formula supplements.

In fact, if you work in a centre that has access to pasteurized donor human milk it is unethical to randomize infants to receive artificial formula as a supplement.

The only justification for giving a preterm baby at risk for NEC artificial formula, rather than donor human milk, if it is available, is parental refusal. And even then, if a parent refused for a baby at very high risk, I think it is questionable whether such a refusal should be accepted.

The other trial (O’Connor DL, et al. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial. Am J Clin Nutr. 2018;108(1):108-16) was very different to Sullivan et al, in that study all the babies received breast milk, either maternal or donor, and were randomized to either HMDF or BMDF (in this case powdered BMDF). This study only included 127 babies, so didn’t have much power to show a difference in NEC, but in fact, the 2 groups had exactly the same number of cases of proven NEC.

The evidence has never shown that adding a powdered multi-component fortifier to mothers milk has an adverse impact on Necrotising Enterocolitis rates, and until recently the only fortifier available was BMDF. That doesn’t mean we have good evidence that they are definitely safe, the Cochrane systematic review shows that the studies that looked directly at the issue only had a rate of NEC of about 2.5%; there was no evidence of a higher risk with the fortifier, but they note that the evidence is weak. The relative risk of NEC comparing fortifier to no fortifier was 1.37 (95% limits 0.72 – 2.63), which means of course that there remains a risk that fortification might substantially increase NEC.

Why not just switch to HMDF anyway? The available HMDF is a liquid, and as such dilutes the mother’s own milk that is given to the baby, for example, the standard fortification of mothers milk requires that there is a dilution of 40 mL of mothers milk by 10 mL of the liquid fortifier.

The ways the various products are produced are quite different, for example, the pasteurization of Prolacta is done by a Vat method, which destroys some of the good proteins (such as lactoferrin) in the human milk. Local milk banks usually use Holder pasteurization which has much less effect on those proteins, and some banks use very short time, higher temperature pasteurization which is probably even better.

I also don’t think there is any good reason to believe that the increase in NEC seen with artificial formula is because of the source of the protein, it could well be other features of preparation, sterilization, manipulation etc. Preterm newborns extremely rarely have evidence of cows milk protein intolerance, in fact, foreign proteins usually induce tolerance when you give them to preterm infants. The focus on where the proteins in the milk come from may be entirely misleading. If we concentrated on why formula increases NEC compared to human milk we might gain some further insights into the pathophysiology of the disease.

Human-milk based fortifier is extremely expensive, but even if it cost the same as the BMDF I think there should be robust evidence before switching to using it. It will require diversion of a significant proportion of our currently available breast milk to create enough fortifier for every baby, and it will reduce the amount of the mother’s own breast milk that a baby receives, by dilution.

In summary, the only data that compares BMDF to HMDF in babies receiving maternal breast milk supplemented with donor milk when required (the current standard of care) does not show any difference in Necrotising Enterocolitis. Given the small sample size of that trial and the importance of NEC, I think that performance of a large multi-centre trial is urgent. It should be performed in infants at significant risk who are also receiving all evidence-based preventive methods, multicomponent probiotics and feeding protocols.

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.

6 Responses to Breast milk fortifiers, a new systematic review

  1. Stephen Moffitt MD says:

    The question that I have is whether or not there is a difference between the powdered HMF and the newer extensively hydrolyzed liquid HMF, which do not contain intact the fully intact cow milk proteins. There might be an advantage with a human milk based oligosaccharide profile versus a cow based profile.

    • I have the same question, the simple answer right now is, I think, that we don’t know. I do think there are likely to be differences, and the powdered preparations have changed and are now at least partially hydrolyzed. I agree also about the oligosaccharides, that might be why formula feeding increases NEC because the lack of HMOs impact the microbiome, and maybe if you are already getting all human milk it doesn’t matter that there are additional bovine MOs in the fortifier. Maybe.

  2. IL says:

    There is a UK consultation at the moment about a plan for a large cluster RCT (3700 infants <29 weeks) planning to look at two comparators: supplementing shortfall of MOM with either donor milk or preterm formula; and routine fortification (presumably bovine origin) or no routine fortification. Proposed outcomes are survival to 36wk PMA without NEC surgery and survival to 2 years without moderate to severe neurodevelopmental impairment. I'm interested in your thoughts on this?

    • I would be very concerned about the first comparison, I think the issue of supplementing a shortfall of MOM with donor milk or formula is settled. I have gone as far as to say that such a trial would be unethical. I think we can say with a high degree of certainty that using donor milk in that situation leads to less NEC than formula.
      I am also concerned about the idea of a group without “routine” fortification. Can you really envisage putting a 24 week 600g baby on a diet without fortification? Even if they tolerate 220 mL/kg/d of milk, they will still be very low on phosphate intake, low on calcium and protein. You risk having an enormous rate of postnatal growth retardation, and some very malnourished babies. I think the question is whether bovine fortifiers are safe could be answered maybe with less risk if the controls received phosphate, calcium and maybe a hydrolysed protein source, or human milk-derived fortifier if you can find an affordable source.

  3. We addressed the same core issues about comparisons narrowed to fortifiers without the confounding effect of formula in our Cochrane Review. Premkumar MH, Pammi M, Suresh G. Human milk-derived fortifier versus bovine milk-derived fortifier for prevention of mortality and morbidity in preterm neonates. Cochrane Database Syst Rev. 2019;2019(11):CD013145. Published 2019 Nov 7.

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