Short summary

The purpose is to investigate the safety, tolerability and the preliminary effects of bovine colostrum used as human milk fortifier for mother's milk and/or donor milk in very preterm infants (gestational age 26+0 to 30+6). This multicenter, non-blinded, randomized pilot study will be conducted at six neonatal units in Denmark and two neonatal units in China: Aarhus University Hospital, Herlev Hospital, Hvidovre Hospital, Kolding Hospital, Odense University Hospital, Rigshospitalet, Nanshan People's Hospital and Baoan Maternal and Children's Hospital.

Rationale

Very preterm infants (less than 32 weeks gestation) are born with immaturity of many organs and have a relatively high nutrient requirement for growth and development compared to infants born mature. Poor growth in the postnatal period of such infants is associated with later impaired neurodevelopment. Slow growth interact closely with other complications of preterm birth, but provision of adequate energy and nutrients (e.g. protein, minerals, vitamins) improves the clinical outcomes both during hospitalization and later in life. Parenteral nutrition (PN) may initially be needed to support nutrient intake in these infants, but fast transition to enteral nutrition (EN) is important to improve gut maturation and later growth. On the other hand, too fast increase in enteral feeding and growth may predispose to feeding intolerance, necrotizing enterocolis (NEC) and late onset sepsis (LOS). It therefore remains a difficult task to optimize the transition to EN.

Mothers own milk (MM) is considered the best source of EN for preterm infants, however, very often is MM insufficient in amount, or not available, during the first weeks after preterm birth. If MM is not sufficient donor milk (DM) is used as the second choice, if available. However both milk types do not contain enough protein to achieve a postnatal growth rate similar to the intrauterine growth rate. On this background, it has become standard practice to enrich MM and DM with human milk fortifiers  (HMF), which contains extra amount of proteins, to support the growth, bone mineralization and neurodevelopment of preterm infants.

There have been concerns that currently available HMFs, based mainly on bovine milk products, increase feeding intolerance and risk of NEC due to previous studies concerning this matter. It is well documented that an infant formula is inferior to MM for preterm infants, but it remains unclear if addition of HMFs to MM and DM constitutes a separate risk factor.

Bovine colostrum is the first milk from cows after parturition and is a rich source of protein and bioactive components. These components may improve gut maturation, protection and nutrient assimilation. Our unpublished data from preterm pigs show that human milk fortified with bovine colostrum improves growth, gut maturation and NEC/LOS resistance during the first 1-2 weeks, relative to supplementation with conventional HMFs.

On this background, we suggest that bovine colostrum, used as a HMF, is a better alternative than currently available HMFs, to support growth, development and NEC/LOS resistance in very preterm infants. This has never been investigated before and a pilot trial is required to test the feasibility, safety and endpoints for a possible later and larger randomized controlled trial. Thus, we aim to investigate the effects of bovine colostrum, used as a fortifier to MM and DM in a pilot study across two continents. The study will investigate growth, NEC and LOS together with a series of para-clinical variables. The results will be used to evaluate effect size, primary outcomes (e.g. NEC- and LOS-free survival at discharge) and secondary outcomes for a later, larger randomised controlled trial.

Description of the cohort

Very preterm infants born between gestational age 26+0 and 30+6 weeks, feed with mother's milk and/or donor milk and in need of fortification, and treated at one of the participating hospitals.

Data and biological material

Clinical data will be obtained from medical records and case report forms. For example, data will be collected about birth, hospitalization, complications, anthropometry, and nutrition. Furthermore, in both groups blood and fecal samples will be collected at three times point during the intervention (day 0, 7 and 14). 

Collaborating researchers and departments

Department of Neonatology, Hans Christian Andersen Children's Hospital, Odense University Hospital

• Gitte Zachariassen
• Nana Hyldig

Department of Comparative Pediatrics and Nutrition, University of Copenhagen

• Per Torp Sangild
• Agnethe Ahnfeldt

Department of Neonatology, Rigshopitalet

• Susanne Søndergaard Koppel

Department of Neonatology, Aarhus University Hospital

• Bente Høst

Department of Neonatology, Herlev Hospital

• Bø Mølholm Hansen
• Sussie Andersen

• Heidi Smedegaard

Department of Neonatology, Kolding Hospital

• Anja Klamer

Department of Neonatology, Nanshan People's Hospital

•  Xiaodong Li
• Zhongqian He

Department of Neonatology, Baoan Maternal and Children's Hospital

• Ping Zhoug