TITLE OF STUDY: Safety and Efficacy of a Novel Human Milk-based Human Milk Fortifier in Very Low Birth Weight Infants

Background Once feeding low birthweight (LBW) or very low birthweight (VLBW) infants was primarily by commercial specialty formulas. As public health emphasis on breastfeeding increased awareness and prevalence of breastfeeding, the use of human milk in the Neonatal Intensive Care unit (NICU) became more common. However, despite the fact that milk from mothers delivering prematurely has higher nutritional content than milk from mothers delivering at term, mainly in protein and fat, thus calories, nutrient intake from human milk alone is not sufficient to satisfy the nutrition of the LBW or VLBW infants and support intrauterine growth rates. Low birth weight infants have faster growth when fed preterm formula compared to when they are breastfed. Consequently, human milk fortifiers (HMF) with an emphasis on protein and caloric density (to accommodate small gastric volume among these babies) but with major minerals and selected micronutrients were developed as supplements to admix with human milk for feeding preterm infants. HM fortifiers were initially based on cows milk proteins and were manufactured as either powders or liquids, the latter having the benefit of being sterile, avoiding the risk of contamination by bacterial contaminants in powders, eg, cronobacter sakazakii. Attention to early life nutrition has reduced the prevalence of growth restricted infants at discharge.

Protein Increased protein in fortifiers in LBW feeds directly improves weight gain, and early introduction of fortifiers may mitigate typical protein intake shortfall that is seen during the transition from parenteral to enteral feeding. The highest useful protein level may have been determined.Growth of VLBW infants fed primarily breast milk supplemented with bovine milk fortifier to obtain 4.3 g protein/kg/d was not improved over infants whose milk fortification was 3.7 g/kg/d; both groups nearly achieved intrauterine growth rates. Breast milk comprised 92 and 94% of total food intake and average daily weight gains were 16.3 g/kg and 16.0 g/kg in the lower and higher protein groups, respectively. Length and head circumference gains were similar between groups. In one study bovine based fortifier providing total protein at a yet higher level of 4.6- 5.4 g/kg/d reported improved length gain, but not weight gain.

Other variations of protein presentation also have been reported. Liquid HMF made with extensively hydrolyzed protein at 3.6g/100 kcal gave slightly better weight gain than powdered intact protein containing 3 g protein/100 kcal. A new powdered presentation using partially hydrolysed whey protein at 16% higher total protein content than the commercial product with intact protein gave improved weight gain. In addition to the protein content, processing is important. Acidified liquid fortifier-fed infants fared poorer than infants fed neutral pH sterilized HMF even though the acidified formula had higher protein intake (4.2 g/kg) than the sterilized (3.7 g/kg).

None of these studies assessed the effects of different levels of human milk protein, but they suggest attention be paid to achieving protein targets; that liquids may be preferred over powders, and that sterilized neutral pH products are preferable to acidified products.

Necrotizing enterocolitis (NEC) One study created awareness about the value of feeding exclusive human milk in the NICU and reported that there was no difference in growth between VLBW infants fed mothers own milk supplemented with a fortifier derived from donor human milk or when a fortifier based on bovine milk was used, though the exclusively human milk diet resulted in fewer cases of NEC and NEC requiring surgical intervention. Subsequently, another study reported feeding with a fortifier based on human milk reduced days of parenteral nutrition (p=0.04), trend toward all NEC (p= 0.08) and reduced surgical NEC (p=0.04) when compared to fortification with preterm bovine milk based formula. Others report the timing of onset of NEC was delayed and incidence of late onset NEC (after 7 feeding days) and incidence of sepsis was significantly reduced among infants fed exclusive human milk diets compared to an earlier cohort of infants supplemented with bovine products; however, respiratory distress syndrome and use of surfactants was more common among the exclusive human milk cohort, and infants fed bovine products were more commonly discharged to home. A 2014 Cochrane review of 9 studies found an increased risk of NEC among infants fed preterm formulas. This conclusion has been supported by recent retrospective studies, and extending benefit of exclusive human milk diets to reduced risk of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) in addition to NEC .