Bovine Colostrum as a Fortifier Added to Human Milk for Preterm Infants
Condition: Growth; Necrotizing Enterocolitis; Late-Onset Sepsis; Feeding Intolerance
MeSH terms: Enterocolitis; Enterocolitis, Necrotizing
Study type: Interventional

Summary: 
      Very preterm infants (<32 weeks gestation) with very low birth weight (VLBW, <1500 g) show
      immaturity of organs and have high nutrient requirements forgrowth and development. In the
      first weeks, they have difficulties tolerating enteral nutrition (EN) and are often given
      supplemental parenteral nutrition (PN). A fast transition to full EN is important to improve
      gut maturation and reduce the high risk of late-onset sepsis (LOS), related to their immature
      immunity in gut and blood. Conversely, too fast increase of EN predisposes to feeding
      intolerance and necrotizing enterocolitis (NEC). Further, human milk feeding is not
      sufficient to support nutrient requirements for growth of VLBW infants. Thus, it remains a
      difficult task to optimize EN transition, achieve adequate nutrient intake and growth, and
      minimize NEC and LOS in the postnatal period of VLBW infants.

      Mother´s own milk (MM) is considered the best source of EN for VLBW infants and pasteurized
      human donor milk (DM) is the second choice, if MM is absent or not sufficient. The
      recommended protein intake is 4-4.5 g/kg/d for VLBW infants, when the target is a postnatal
      growth similar to intrauterine growth rates. This amount of protein cannot be met by feeding
      only MM or DM. Thus, it is common practice to enrich human milk with human milk fortifiers
      (HMFs, based on ingredients used in infant formulas) to increase growth, bone mineralization
      and neurodevelopment, starting from 7-14 d after birth and 80-160 ml/kg feeding volume per
      day. Bovine colostrum (BC) is the first milk from cows after parturition and is rich in
      protein (80-150 g/L) and bioactive components. These components may improve gut maturation,
      NEC protection and nutrient assimilation, even across species. Studies in preterm pigs show
      that feeding BC alone, or DM fortified with BC, improves growth, gut maturation and NEC
      resistance during the first 1-2 weeks, relative to DM, or DM fortified with conventional
      HMFs.On this background, we hypothesize that BC, used as a fortifier for MM or DM, can induce
      similar growth and better NEC and LOS resistance, than conventional fortifiers. A pilot trial
      is required 1) to test the feasibility and initial safety of BC as a fortifier (e.g. similar
      growth rates and clinical variables as conventional fortification), 2) to calculate the
      sample size for a later, larger RCT with NEC +LOS as the primary outcome, and 3) record
      paraclinical outcomes associated with type of fortifier.
    

Detailed description: 
      The main objectives of this multicentre, non-blinded, pilot, RCT are:

        1. To investigate the safety, tolerability and the preliminary effects of BC, used as an
           HMF for MM and DM in very preterm infants.

        2. To facilitate the determination of sample size for a later, larger RCT with NEC- and
           LOS-free survival as the primary outcome.

        3. To assess the feasibility of study procedures, incl. recruitment rates, parental
           consent, adherence, sample collection, and clinical routines.

      Participants Parents to eligible very preterm infants admitted to the Neonatal Intensive Care
      Units (NICU) at Nanshan People's Hospital (NAN) and Baoan Maternal and Children's Hospital in
      Shenzen, China will be asked for participation.

      Since this is a pilot trial, a conventional sample size calculation, using only one primary
      outcome, is not required. The aim is to include 200 infants (100 per group), which is
      expected to give sufficient strength to demonstrate effects on the chosen feasibility
      outcomes and secondary blood and stool variables (see protocol). Statistical analyses will be
      performed blindly on both intention-to-treat and per protocol basis. Continuous outcomes will
      be summarized as mean and standard deviation (e.g., body weight) or median and interquartile
      range (e.g. time to reach full enteral feeding). Binary outcomes (e.g. incidence of NEC) will
      be presented as counts and percentages. To test the preliminary effects of BC, clinical and
      para-clinical outcomes will be compared between the two groups. The estimates will be
      presented as relative risk and absolute risk difference, difference between means, or hazard
      ratio, depending on the type of outcome. The estimates will be presented with a 95%
      confidence interval. Further statistical analyses are described in the protocol.
    

Intervention name(s): Bovine Colostrum (BC) / intervention group; FM85 / control group
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Infants randomized to the intervention group will receive a maximum of 2.8 g bovine colostrum (BC, Biofiber, Gesten, Denmark), as the HMF added to 100 ml of MM and/or DM, when EN has reached a dose of 100-140 ml/kg/d and blood urea nitrogen (BUN) levels are below 5 mmol/l.
The infants starts with 1 g (0.5 g protein) BC per 100 ml human milk on the first day, increased to 2 g (1.0 g protein) on day 3, and finally 2.8 g (1.4 g protein) on day 5, if the infants only receive DM.
The intervention begins if the infants meet the inclusions criteria and the intervention lasts until the infants reach post menstrual age (PMA) 34+6 weeks or are discharged home (including participating in an "early discharge program"), or are transferred to non-participating neonatal units, whichever comes first.; Infants randomized to the control group will receive a maximum of 4 g PreNAN FM85 (Nestlé, Vevey, Switzerland) as HMF, added to 100 ml MM and/or DM, when EN has reached a dose of 100-140 ml/kg/d and BUN levels are below 5 mmol/l.
The infants starts with 1 g (0.35 g protein) FM85 per 100 ml human milk on the first day, which will be increased to 3 g (1.05 g protein) on day 3 and finally 4 g (1.4 g protein) on day 5, if the infants only receive DM.
FM85 is the standard HMF used in all participating hospitals in Denmark. The infants will receive FM85 as the HMF as long as additional protein in the milk is needed.
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: A multicentre, non-blinded, pilot randomized controlled trial
Masking: Single (Outcomes Assessor)
Primary purpose: Supportive Care
Keywords: Human Milk Fortification; Bovine Colostrum; Very Preterm Infants; Enteral feeding; Human Milk; Neonatology; Colostrum