Novel Human Milk Based Human Milk Fortifier
Novel Human Milk Based Human Milk Fortifier
The primary objective is to assess weight gain of VLBW infants fed human milk supplemented
 with a novel human milk-based fortifier, in comparison to use of other fortifiers (historic
 controls).
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 .

 The value of exclusive human milk feeding also has been explored regarding growth. Questions
 of the relative value of mother's own milk compared to donor human milk, the form of
 fortifier (powder v liquid, v acidified liquid), the level of protein, and the source of
 protein (bovine or human) have been explored. A study reported that infants fed >75% donor
 milk had higher risk of small for gestational age (SGA) compared to those fed their own
 mothers milk. Donor milk fed infants had lower weight gain than infants fed either moms own
 milk or preterm formula possibly because of lower nutrient content of donor milk. In
 contrast, VLBW infants fed their own mother's milk fortified alternatively with donor milk or
 preterm formula grew better (weight gain from birth to discharge) as the proportion of diet
 as breast milk increased from <25%, 25-50%, to > 75% of total intake. A retrospective
 analysis among extremely low birthweight infants (ELBW) exclusively human milk diets reported
 a comparable growth and neurodevelopment as infants fed bovine milk based fortifiers.

 Consequently, there is good evidence that fortification of human milk is needed to support
 growth of LBW and VLBW infants, that higher protein up to about 4.3 g/kg/d supports more
 rapid growth, and that risk of NEC and other diseases affecting LBW infants is less when LBW
 infants are fed exclusive human milk diets. The difficulties have been to obtain liquid
 fortifier derived from human milk, and evaluate its use at the protein concentrations that
 have been evaluated using bovine-based products. This study addresses these two needs: a
 sterile liquid fortifier derived from human milk is evaluated at protein intakes recommended
 by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN),
 4.0-4.5 g/kg/d for infants less than 1000g, and 3.5-4.0 g/kg for infants 1000-1800g.

 Summary of Nonclinical Experience with MHMHMF The preclinical experience with this particular
 fortifier is limited to analytical evaluation. There are no suitable animal models sensitive
 to testing the biological source of the protein, and no alternative method for assessing
 growth of infants fed a human protein-based fortifier than clinical study. The protein
 quality of the processed protein has been established by amino acid analysis to be close to
 the native protein, with up to a 15% decrease in available lysine, probably due to Maillard
 reaction with lactose. The fortifier, even at its lowest recommended use rate represents more
 than a 2-fold increase in all amino acids when compared to raw breast milk, we are not
 concerned about protein quality with our manufacturing process. Additionally, the composition
 of the blended fortifier exceeds Codex reference for protein quality for infant formula and
 formulas for special medical purposes intended for infants.

 Summary of Clinical Experience Medolac has processed donor whole human milk for feeding LBW
 infants for some years. More recently Medolac has applied standard dairy processes to
 partition milk into milk fat and skim fractions, and to enrich the protein content. The
 processes have allowed the development of high protein human milk fortifier. Supplementation
 of the high protein fraction with vitamins and minerals has resulted in a novel human milk
 based human milk fortifier for fortification of human milk-fed VLBW infants. This is the
 first clinical evaluation of the MHMHMF fortifier. Only one other fortifier derived from
 human milk is available commercially (Prolacta). Reports on its use have been published
 showing reduced days of parenteral nutrition (p=0.04), trend toward all NEC (p= 0.08) and
 reduced surgical NEC (p=0.04) and rescue from failure after use of bovine based fortifiers.

 Description of Investigational Product The investigational product is manufactured from whole
 human breast milk with the addition of selected vitamins and minerals. The source of human
 milk is full lactation, full term donor milk from Mothers Milk Cooperative (Boulder City,
 NV), collected according to stringent blood screening criteria and quality control
 procedures, including microbiological evaluation, nutritional composition and chemical
 analyses. A fractionated, concentrated product is created by first delipidating then
 filtering through ultrafiltration (UF) membranes to selectively concentrate protein with loss
 of low molecular weight components such as lactose and minerals. Fat, selected minerals, and
 vitamins are added to the protein enriched fluid to reach a standard ratio. It is then
 packaged and processed by heat to achieve commercial sterility, granting room temperature
 storage with extensive shelf-life.

 Various blending ratios of the fortifier with either the mother's expressed milk or donor
 milk can be used to deliver varying concentrations of vitamins, minerals, and macronutrients
 enabling nutrient delivery to be adjusted according to the infant's tolerance for volume and
 calories.

 Blending ratios are illustrated in the table below. Simple blending of 50:50 results in a
 high protein, fat enriched fortifier having a caloric density of 27 kcal/ounce with protein
 provided at 3.0g/100 milliliters (mL). When this fortifier is mixed in a 1:2 ratio, the
 resulting caloric density is 25 kcal/oz and protein is provided at 2.4 g/100 ml; when this
 fortifier is mixed in a 1:3 ratio, the resulting caloric density is 23.6 kcal/oz and protein
 is provided at 2.07 g/100 ml; Similarly, other nutrients are delivered as a function of the
 ratio of MHMHMF to human milk.

 The primary objective for growth with this fortifier is the delivery of protein and calories,
 however we recognize that some vitamins are cofactors of enzymes involved in protein and
 energy metabolism. Some minerals such as zinc is variable in human milk, so was selected for
 addition. Other vitamins and minerals such as iron are generally monitored while others such
 as copper, vitamin A, and niacin are not considered limiting in human milk. In addition, heat
 processing used to achieve commercial sterility degrades some vitamins, making separate
 administration desirable. For these reasons the MHMHMF is not comprehensive in its delivery
 of vitamins and minerals which have been shown to be essential for nutrition. Infants should
 be monitored for adequate nutrition and additional fortification given as needed.
Inclusion Criteria:

 -  Birth weight between 750 g-1500 g.

 -  ≤ 32 weeks gestational age at birth. GA will be determined by an ultrasound scan or
 the neonatologist's estimate, with consideration to maternal date.

 -  Subject has been classified as appropriate for GA (AGA).

 -  Enteral feeding of human milk must be initiated by 21 days of life for infants with a
 birthweight of 750-1000 g (birth date is day of life 0) and initiated by 14 days of
 life for infants with a birthweight of 1.0 - 1.5 kg birthweight.

 -  Mother agrees to feed the infant human milk as the exclusive feeding during the study
 period. Human milk may be mothers own or donor milk, plus MHMHMF.

 -  Singleton or twin births only.

 Exclusion Criteria:

 -  Serious congenital abnormalities or underlying disease that may affect growth and
 development.

 -  5 minute APGAR: 5 4.

 -  Steroids used within the past 5 days

 -  Grade Ill or IV periventricular/ intraventricular hemorrhage (PVH/IVH).

 -  Maternal cocaine, alcohol or opioid abuse during pregnancy or currently or if the
 mother or infant is currently receiving treatment for HIV infection.

 -  Infant major surgery (intra-thoracic or intra-abdominal procedures or other surgery
 requiring general anesthesia).

 -  Asphyxia defined as progressive hypoxemia and hypercapnia with significant metabolic
 acidemia characterized by APGAR score <3 at 10 minutes, seizures within the first 12
 hours of life, or a cord blood gas < 7.0 and seizures and/or severe tonic
 abnormalities in the first 12 hours of life.

 -  Infant has any other condition that, in the opinion of the investigator, compromises
 the ability to draw inference about the ability of the MHMHMF to support growth.