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NCT Number: NCT03822104

Bovine Colostrum as a Human Milk Fortifier for Preterm Infants

Very preterm infants (<32 weeks gestation) show the immaturity of organs and have high nutrient requirements for growth 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 very preterm 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 very preterm infants. Mother´s own milk (MM) is considered the best source of EN for very preterm 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 very low birth 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, the investigators hypothesize that BC, used as a fortifier for MM or DM, can reduce feeding intolerance than conventional fortifiers.

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Key information

Conditions

Feeding Intolerance Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Enterocolitis Enterocolitis, Necrotizing Gastroenteritis Gastrointestinal Diseases Infant, Newborn, Diseases Infections Inflammation Intestinal Diseases Late-Onset Neonatal Sepsis Necrotizing Enterocolitis Neonatal Sepsis Pathologic Processes Pathological Conditions, Signs and Symptoms Postnatal Growth Sepsis Systemic Inflammatory Response Syndrome

Age range

5 day–3 week

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Shenzheng Baoan Maternity and Child Healthcare Hospital (SBMCH), Shenzhen, Guangdong, China

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About this study

Objectives

  • To test if fortification of human milk with BC reduces feeding intolerance compared with currently used HMF.
  • To verify the safety and tolerability of BC fortification and to monitor the rates of growth, NEC and sepsis, as investigated in a parallel trial in Denmark

Trial design This study is a dual-center, non-blinded, two-armed, randomized, controlled trial.

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 Shenzhen, China will be asked for participation.

Sample size 68 infants per group, 136 in total

Data type Clinical data

A parallel trial on BC used as human milk fortifier is conducting in Denmark (NCT03537365)

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Very preterm infants born between gestational age 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
  • Signed parental consent

Exclusion criteria

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

Treatment and study plan

Bovine colostrum

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 80-100 ml/kg/d. The infants start 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 lasts until the infants reach postmenstrual age (PMA) 35+6 weeks or in no-need of fortification due to sufficient growth, whichever comes first.

FM85

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 80-100 ml/kg/d. 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. The infants will receive FM85 as the HMF as long as additional protein in the milk is needed until discharge.

Primary outcomes

  1. Incidence of feeding intolerance

    Time frame: From start of intervention until the infants reach PMA 35+6 weeks or are not in need of fortification due to sufficient growth, whichever comes first

    Number of infants in each group diagnosed with feeding intolerance for at least once. Feeding intolerance is defined as any pause of fortification or withhold of enteral feeding.

Secondary outcomes

  1. Body weight

    Time frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks

    Weight gain in grams per kg body weight from birth to discharge. 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.

  2. Body length

    Time frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks

    Recorded as a measure of growth in cm by standardized measuring procedures

  3. Head circumference

    Time frame: Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks

    Recorded as a measure of head growth in cm by standardized measuring procedures

  4. Incidence of necrotizing entercolitis (NEC)

    Time frame: From the start of intervention to hospital discharge, or up to 14 weeks

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

  5. Incidence of late-onset sepsis (LOS)

    Time frame: From the start of intervention to hospital discharge, or up to 14 weeks

    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)

  6. Time to reach full enteral feeding

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Number of days to full enteral feeding is reached - defined as the time when >150 ml/kg/d is reached and parenteral nutrition has been discontinued

  7. Days on parenteral nutrition

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Number of days that the infant receives intravenous intakes of protein and/or lipid and/or glucose

  8. Length of hospital stay

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Number of days in hospital, defined as days from birth until final discharge

Other outcomes

  1. Volume of gastric residual

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Volume of aspirated gastric residuals in ml

  2. Color of gastric residual

    Time frame: From birth to hospital discharge, or up to 14 weeks

    The color of aspirated gastric residuals categorized into 7 colours

  3. Incidence of bloody gastric residual

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Number of infants in each group have had blood in the gastric residual

  4. Frequency of stool per day

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Frequency of stool passed each day

  5. Amount of the stool

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Using a 4-level pre-defined scale Amount of stool on the diaper: the percentage of area covered by stool on the diaper.

    • 1 smear;
    • 2 up to 25%;
    • 3 25-50%;
    • 4 >50%

  6. Color of the stool

    Time frame: From birth to hospital discharge, or up to 14 weeks

    The color of stools categorized into 6 colors

  7. Consistency of the stool

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Using a 4-level pre-defined scale

  8. Total daily volume of enteral nutrition (EN) and parenteral nutrition (PN)

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Volume of EN (including MM, DM, infant formula, and fortification) and PN in take

  9. Levels of macronutrients intake from EN and PN

    Time frame: From birth to hospital discharge, or up to 14 weeks

    Calculated based on the volume and composition of EN and PN

Sponsors and collaborators

Lead sponsor

Per Torp Sangild

Other

Registry information

Official study title

Bovine Colostrum to Fortify Human Milk for Preterm Infants: A Randomized, Controlled Trial

Acronym: FortiColos-Ⅱ

Important dates

Study start
2019
Primary completion
2021
Study completion
2021
First posted
Jan 30, 2019
Registry last updated
Jan 28, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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