Bovine Colostrum as a Human Milk Fortifier for Preterm Infants (FortiColos-Ⅱ)

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

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.

Study Overview

• Status: Completed
• Conditions: Necrotizing Enterocolitis; Feeding Intolerance; Postnatal Growth; Late-Onset Neonatal Sepsis
• Intervention / Treatment: Dietary supplement: Bovine Colostrum; Dietary supplement: FM85

Detailed Description

Objectives

1. To test if fortification of human milk with BC reduces feeding intolerance compared with currently used HMF.
2. 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)

• Study Type: Interventional
• Enrollment (Actual): 139
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Shenzhen, China
    • Shenzhen Nanshan People's Hospital
  • Guangdong
    • Shenzhen, Guangdong, China, 518133
      • Shenzheng Baoan Maternity and Child Healthcare Hospital (SBMCH)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 days to 3 weeks (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. 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)
2. DM is given at the unit when MM is absent (or insufficient in amount)
3. 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
4. Signed parental consent

Exclusion Criteria:

1. Major congenital anomalies and birth defects
2. Infants who have had gastrointestinal surgery prior to randomization
3. Infants who have received IF prior to randomization

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bovine Colostrum / intervention group; 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; 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.
Active Comparator: FM85 / control group; 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; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of feeding intolerance	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.	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Body weight	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.	Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks
Body length	Recorded as a measure of growth in cm by standardized measuring procedures	Measured weekly from the start of intervention until hospital discharge, or up to 14 weeks
Head circumference	Recorded as a measure of head growth in cm by standardized measuring procedures	Measured weekly from the start of intervention until 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 the 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 the start of intervention to hospital discharge, or up to 14 weeks
Time to reach full enteral feeding	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	From birth to hospital discharge, or up to 14 weeks
Days on parenteral nutrition	Number of days that the infant receives intravenous intakes of protein and/or lipid and/or glucose	From birth to hospital discharge, or up to 14 weeks
Length of hospital stay	Number of days in hospital, defined as days from birth until final discharge	From birth to hospital discharge, or up to 14 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volume of gastric residual	Volume of aspirated gastric residuals in ml	From birth to hospital discharge, or up to 14 weeks
Color of gastric residual	The color of aspirated gastric residuals categorized into 7 colours	From birth to hospital discharge, or up to 14 weeks
Incidence of bloody gastric residual	Number of infants in each group have had blood in the gastric residual	From birth to hospital discharge, or up to 14 weeks
Frequency of stool per day	Frequency of stool passed each day	From birth to hospital discharge, or up to 14 weeks
Amount of the stool	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%	From birth to hospital discharge, or up to 14 weeks
Color of the stool	The color of stools categorized into 6 colors	From birth to hospital discharge, or up to 14 weeks
Consistency of the stool	Using a 4-level pre-defined scale	From birth to hospital discharge, or up to 14 weeks
Total daily volume of enteral nutrition (EN) and parenteral nutrition (PN)	Volume of EN (including MM, DM, infant formula, and fortification) and PN in take	From birth to hospital discharge, or up to 14 weeks
Levels of macronutrients intake from EN and PN	Calculated based on the volume and composition of EN and PN	From birth to hospital discharge, or up to 14 weeks

Collaborators and Investigators

• Sponsor: Per Torp Sangild
• Investigators: Study Chair: Per T Sangild, Rigshospitalet, Denmark; Principal Investigator: Ping Zhou, Shenzheng Baoan Maternity and Child Healthcare Hospital

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2019
• Primary Completion (Actual): June 13, 2021
• Study Completion (Actual): July 8, 2021

Study Registration Dates

• First Submitted: January 17, 2019
• First Submitted That Met QC Criteria: January 28, 2019
• First Posted (Actual): January 30, 2019

Study Record Updates

• Last Update Posted (Actual): January 28, 2022
• Last Update Submitted That Met QC Criteria: January 13, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Nutrition; Human milk; Very Preterm Infants; Human Milk Fortifier; Bovine Colostrum; Enteral Feeding
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Infections; Systemic Inflammatory Response Syndrome; Inflammation; Gastrointestinal Diseases; Infant, Newborn, Diseases; Gastroenteritis; Intestinal Diseases; Sepsis; Enterocolitis; Enterocolitis, Necrotizing; Neonatal Sepsis
• Other Study ID Numbers: FortiColos-CN

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No