Early Routine vs. Selective Human Milk Fortification in Extremely Preterm Infants

II. BACKGROUND Necrotizing enterocolitis (NEC) is a serious gastrointestinal disease affecting >10% of extremely preterm infants with a mortality of up to 50%. The pathophysiology is poorly understood, but intestinal immaturity, microbial colonization, hypoxic ischemia, and diet have all been implicated. Use of human milk and standardized feedings are the only strategies that consistently have been shown to decrease the incidence of disease. Our NICU has been using a standardized feeding protocol with an emphasis on human milk for over 20 years. In 1995, Crouse became a NY state licensed human milk bank, which accepts donors that have delivered preterm. Preterm breast milk has distinct nutritional advantages over milk obtained from donors who delivered term infants. In particular, there is a higher protein and mineral concentration in preterm human milk compared to mature term milk which is what is typically available in all commercial milk banks. All extremely preterm infants in our NICU receive preterm human milk - maternal or donor. Combined with following our standard feeding protocol, this has resulted in >90% less NEC than in comparable NICUs. The investigators reported an incidence of NEC of 1% over a recent 6 year period, compared to an incidence of 12% among the three other upstate NY regional perinatal programs (Albany, Rochester and Buffalo).

While the prevention of feeding related morbidities such as NEC is paramount, growth remains a concern in these extremely preterm infants. Growth velocity has been shown to have a significant effect on neurodevelopmental outcomes in at least one study. Human milk fortifiers are marketed and used to various degrees in an effort to increase weight gain in VLBW infants fed maternal breast milk (MBM). Our current feeding protocol calls for "selective" human milk fortification with a human milk derived fortifier (HMDF; Prolact+4 H2MF, Prolacta Bioscience, Morovia, CA). Our criterion for fortification is sustained weight gain <15 g/kg/day. Most other centers use fortification more routinely. The impact of fortification on feeding related morbidities (e.g. NEC) as well as growth and longer term outcomes are unknown. For example, one recent randomized trial included infants at high risk for NEC (birth weight <1250 g). All of the infants in that study were fed their own mother's milk but differed by the type of supplementation used. Some infants received HMDF (Prolacta) and donor human milk if maternal milk became unavailable (exclusive human milk diet), whereas others received a bovine milk-based fortifier with maternal milk and preterm formula if no maternal milk was available (bovine group). In the exclusive human milk group, some infants were assigned randomly to receive fortification early (when milk intake was only 40 mL/kg/day) and some later (when milk intake was 100 mL/kg/day). While the incidence of NEC was reduced from 26% for infants in the bovine group to 7% for those in the exclusive human milk group , the incidence was still seven-fold higher than that reported by us. Also of note, the group who received the earlier fortification had a higher incidence of NEC than the group that received later fortification (8% vs 6%). It is unclear what role early fortification plays in the pathogenesis of NEC, but theoretical concerns include effects on host-defense properties and milk osmolality.

In summary:

1. Exclusive use of human milk is associated with a lower rate of NEC.
2. Preterm human milk (maternal or preterm donor) has distinct advantages over commercial donor human milk that comes from mothers of mature term infants.
3. Fostering more rapid growth seems advantageous, but the role of fortification in the development of NEC and other morbidities is unclear as are the long term benefits.

Therefore, the purpose of our study is to compare an exclusive preterm human milk diet using routine early fortification with a diet that uses fortification selectively for poor growth.