Effectiveness of Human Milk-Based Fortifiers for Preventing Necrotizing Enterocolitis in Preterm Infants: Case Not Proven

Dear Editor:

We read with interest the article by Ganapathy et al. ¹ that attempted to determine the cost-effectiveness of a 100% human milk (HM) diet versus a diet that includes bovine milk protein in preterm infants. The benefit of a 100% HM diet is based on a key article published by Sullivan et al. ² in 2010 in which babies whose mothers intended to feed them their own milk were randomized to a HM-based or a bovine milk-based fortifier and milk supplement. When there was insufficient mother's own milk, infants in the HM-based arm were supplemented with donor HM, whereas those in the bovine milk group were supplemented with a bovine milk-based formula. It is therefore impossible to determine whether the lower rate of necrotizing enterocolitis (NEC) seen in the HM arm was due to the benefit of the novel HM fortifier or to the benefit of giving HM as opposed to bovine formula milk. There are already data to show that use of bovine formula instead of HM is associated with higher rates of NEC, ³ that fortified HM is associated with less NEC than formula, ⁴ and that higher proportions of HM (despite fortification with bovine milk-based fortifiers) are associated with lower rates of NEC. ⁵

In the trial of Sullivan et al., ² the combined outcome “NEC and sepsis” was one of several secondary outcomes specified. There were no differences between the study arms, but only three of 67 (4.5%) of the HM100 subgroup or five of 71 (7%) of the HM40 subgroup in the HM arms, compared with 11 of 69 (16%) in the bovine milk group, developed NEC. ² Infants in the HM100 group had a nonsignificantly higher rate of late-onset sepsis than those in the bovine milk group (28% versus 19%). The low rate of “NEC surgery” in infants who only received HM is impressive (1.5%), but the background rate of NEC in infants fed according to standard guidelines with bovine milk-based fortifiers (16% all NEC, 12% NEC surgery) is much higher than in many units.

There are several differences among commercially available fortifier preparations. Fortifiers based on hydrolyzed protein are used widely, especially in Europe, and may be less immunogenic than whole protein-based products. North American products tend to have higher levels of calcium (which may increase the risk of insoluble soap formation), and many are iron fortified, whereas many European products do not include iron. All these factors may play a role in the development of NEC.

NEC results in significant long-term morbidity and increased mortality, and any strategy that reduces the incidence is to be welcomed. Given the considerable healthcare burden of NEC, most reduction strategies will likely be cost-effective. However, an unequivocal case for use of a HM fortifier has not been determined. Because NEC affects not only thousands of babies across the United States and Europe, but tens of thousands globally every year, these studies deserve further attention. The company (Prolacta^® Bioscience) that manufactured the HM-based fortifier claims that its product has been “clinically demonstrated to reduce the odds of developing NEC by 77%,” citing the study published by Sullivan et al. ² We urge the company, health research institutes, and regulatory authorities to support a definitive and appropriately powered trial to further test these results using current estimates of NEC incidence. We congratulate the authors of both studies^1,2 for addressing an important issue, but do not believe that the existing evidence supports the current claims of effectiveness.