Bovine Colostrum as a Fortifier Added to Human Milk for Preterm Infants

NCT03537365 | Completed DMC

• 1 other identifier: FortiColos (pilot RCT)
• Study Type: interventional
• Target: 252
• Locations: 1 country
• Sites: 7

Brief 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.

Conditions

Growth; Necrotizing Enterocolitis; Late-Onset Sepsis; Feeding Intolerance

Keywords

Human Milk Fortification; Bovine Colostrum; Very Preterm Infants; Enteral feeding; Human Milk; Neonatology; Colostrum

Outcome Measures

Primary Outcomes (3)

• Body weight

  Weight gain in grams from birth to discharge from hospital. Weight at different time points will be calculated into z-scores according to a reference. Delta z-scores will be used to evaluate growth and for comparison between groups.

  From start of intervention to hospital discharge, or up to 14 weeks

• Incidence of necrotizing entercolitis (NEC)

  Number of infants in each group diagnosed with necrotizing enterocolitis (NEC) defined as Bell's stage II or above (Kliegman \& Walsh 1987).

  From start of intervention to hospital discharge, or up to 14 weeks

• Incidence of late-onset sepsis (LOS)

  Number of infants in each group diagnosed with late-onset sepsis defined as clinical signs of infection \>2 days after birth with antibiotic treatment for ≥5 days (or shorter than 5 days if the participant died) with or without one positive bacterial culture in blood or cerebral spinal fluid (CSF).

  From start of intervention to hospital discharge, or up to 14 weeks

Secondary Outcomes (7)

• Feeding intolerence

  From start of intervention to end of study period at post menstrual age 34+6 weeks, or up to 8 weeks

• Time to reach full enteral feeding

  From birth to full enteral feeding, or up to 8 weeks

• Days on parenteral nutrition

  From birth to end of intervention, or up to 8 weeks

• Length of hospital stay

  From birth until until final discharge, or up to 14 weeks

• Blood urea nitrogen (BUN)

  Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

Other Outcomes (13)

• Body length

  Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

• Head circumference

  Weekly from just before to end of intervention at postmenstrual age 34+6 weeks, or up to 8 weeks

• Plasma amino acid levels

  Prior to and after 1 and 2 weeks of intervention

Study Arms (2)

Bovine Colostrum / intervention group

EXPERIMENTAL

Preterm infants are supplemented with bovine colostrum (BC) as a fortifier to human milk. BC is the first milk from cows after parturition and is a rich source of protein (80-150 g/L) and bioactive components, including lactoferrin, lysozyme, lactoperoxidase, immunoglobulins, and growth factors. The product is supplied in a sterile, powdered form and consists of unmodified, intact BC.

Dietary Supplement: Bovine Colostrum (BC) / intervention group

FM85 / control group

ACTIVE COMPARATOR

Preterm infants are supplemented with PreNAN FM85 as fortifier to human milk. PreNAN FM85 contains partially hydrolyzed protein and maltodextrin including vitamins and minerals. The product is supplied in a powdered form.

Dietary Supplement: FM85 / control group

Interventions

Bovine Colostrum (BC) / intervention group DIETARY_SUPPLEMENT

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.

Bovine Colostrum / intervention group

FM85 / control group DIETARY_SUPPLEMENT

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.

FM85 / control group

Eligibility Criteria

• Age: 5 Days - 3 Weeks
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Very preterm infants born between GA 26+0 and 30+6 weeks (from the first day of the mother's last menstrual period and/or based on fetal ultrasound)
• DM is given at the unit when MM is absent (or insufficient in amount)
• Infants judged by the attending physician to be in need of nutrient fortification, as added in the form of HMF to MM and/or DM
• Infants admitted and staying at participating units at least until post menstrual age (PMA, gestational age + weeks and/or days since birth) 34+6 weeks, before being transferred to non-participating units, or going home participating in an "early discharge program". The infants can be transferred from one participating unit to another participating unit.

You may not qualify if:

• Major congenital anomalies and birth defects
• Infants who have had gastrointestinal surgery prior to randomization
• Infants who have received infant formula prior to randomization

Sponsors & Collaborators

• Per Torp Sangild: lead
• Kolding Sygehus: collaborator
• Herlev Hospital: collaborator
• Hvidovre University Hospital: collaborator
• Aarhus University Hospital: collaborator
• Odense University Hospital: collaborator
• Nordsjaellands Hospital: collaborator

Study Sites (7)

Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Rigshospitalet (RH)

Copenhagen, 2100, Denmark

Location

Herlev Hospital

Herlev, 2730, Denmark

Location

North Zealand Hospital

Hillerød, 3400, Denmark

Location

Hvidovre Hospital (HH)

Hvidovre, 2650, Denmark

Location

Kolding Hospital

Kolding, 6000, Denmark

Location

Odense University Hospital

Odense, 5000, Denmark

Location

Related Publications (3)

• Yang L, Hui Y, Sangild PT, Kot WP, Aunsholt L, Zachariassen G, Jiang P-P, Nielsen DS. Gut microbiota development in very preterm infants following fortification of human milk. mSystems. 2025 Mar 18;10(3):e0091624. doi: 10.1128/msystems.00916-24. Epub 2025 Feb 21.

  PMID: 39982063 DERIVED

• Lewis AE, Kappel SS, Hussain S, Sangild PT, Zachariassen G, Aunsholt L. Trial-related blood sampling and red blood cell transfusions in preterm infants. Acta Paediatr. 2023 Dec;112(12):2486-2492. doi: 10.1111/apa.16948. Epub 2023 Aug 16.

  PMID: 37565393 DERIVED

• Ahnfeldt AM, Hyldig N, Li Y, Kappel SS, Aunsholdt L, Sangild PT, Zachariassen G. FortiColos - a multicentre study using bovine colostrum as a fortifier to human milk in very preterm infants: study protocol for a randomised controlled pilot trial. Trials. 2019 May 22;20(1):279. doi: 10.1186/s13063-019-3367-7.

  PMID: 31118098 DERIVED

MeSH Terms

Conditions

Enterocolitis, Necrotizing

Interventions

Control Groups

Condition Hierarchy (Ancestors)

Enterocolitis; Gastroenteritis; Gastrointestinal Diseases; Digestive System Diseases; Intestinal Diseases

Intervention Hierarchy (Ancestors)

Epidemiologic Research Design; Epidemiologic Methods; Investigative Techniques; Research Design; Methods

Study Officials

• Gitte Zachariassen, MD., PhD

  Odense University Hospital

  PRINCIPAL INVESTIGATOR

• Per Sangild, Prof

  Rigshospitalet, Denmark

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: A multicentre, non-blinded, pilot randomized controlled trial

Study Record Dates

• First Submitted: January 16, 2018
• First Posted: May 25, 2018
• Study Start: December 4, 2017
• Primary Completion: February 28, 2022
• Study Completion: February 28, 2022
• Last Updated: March 23, 2022

Record last verified: 2022-03

Locations

DK (7)