Bovine Colostrum for Preterm Newborns (PreColos-RCT)

The Precolos-RCT is a multicenter, two-arm, unblinded, randomized, controlled trial. Infants are randomized to an intervention group which receives BC and a control group which receives PF. In detail, MM is always the first priority, when available. When MM is not available, or the available amounts do not fulfill the needs, infants in BC group will receive BC and control infants will receive PF, as the supplementary diets. Feeding should be initiated within 24-48 h after birth following a pre-defined nutritional guideline. BC intervention should not exceed postnatal day 14. After the intervention period, the participants in both groups will receive standard feeding which is the available MM with or without supplemental preterm infant formula. Infants will be followed until discharge home or reach a postconceptional age of 37 weeks, whichever comes first (discharge home/37 wks).

In general, parenteral and enteral nutrition should be given according to the following description:

Parenteral and enteral nutrition will be given according to the targeted daily fluid, energy, and protein levels suggested by ESPGHAN and CSPEN. Enteral nutrition should be given according to the feeding guideline and PN is used to ensure the targeted protein, energy, and lipid intake when enteral feeding is insufficient to provide fluid and nutrition. Participating hospitals should try their best to assist mothers in expressing their colostrum and milk and giving mother's colostrum as the first feeds. Enteral feeding should be given as soon as possible within 24h of life after randomization for infants with BW > 750g. For infants with BW ≤ 750 g, first feeding should be given within 24 h if mother's colostrum is available. Otherwise, first feeding should wait until day 2 for mothers to express their own colostrum. Mother's colostrum and MM is given as much as available, and when it is not available or in an insufficient amount, BC or PF is used during the intervention period to supplement the lacking volume. Infants should receive an initial feeding volume of 5-10 ml/kg/d and the volume should increase by 5-20 ml/kg/d until 150-160 ml/kg/d depending on their BW. The advancing rate of feeding should follow the suggested pace but also be adjusted according to the tolerability of the infants. If feeding intolerance occurs, feeding should be at a flat rate or be withheld according to predefined criteria in 'parenteral and enteral nutrition SOP'. If infants can tolerate more, feeding can be increased faster. Since total protein intake should be within 4-4.5 g/kg/d according to the ESPGHAN guideline25, the maximal daily volume of BC should be calculated based on the available volume of MM and protein levels in MM and BC. The protein supply from MM is calculated assuming a protein content of 1.5 g/100 mL27 (during the first 14 days) and the protein supply from colostrum is 8 g/100 mL (may adjust to changes according to the product specification of the batch in use when the difference is bigger than 5%). At the end of the intervention period, the enteral feeding in the intervention group will be gradually transferred to standard feeding (MM with supplemental PF when needed). Participants in the control group will keep receiving standard feeding after the intervention period. However, if a participant reaches term during their hospital stay, PF may be changed to term formulas according to local guidelines. The participating hospitals use four types of PF with similar nutrients composition and will remain the same throughout the study.

Although in the intervention group, infants should receive supplemental BC instead of PF during the intervention period, there is a possibility that PF and BC are simultaneously used as the supplemental diets. For example, when a participant in the intervention group can tolerate a higher EN volume than the available volume of MM plus the maximum daily volume of BC (due to max protein limitation), PF needs to be given to fulfill the total EN volume. Importantly, the volume of each milk diet will need to be adjusted according to the maximal protein intake of 4-4.5 g/kg/d. When BC intake has reached the maximal volume due to protein limitation but fluid requirement still needs to be fulfilled by PN, the PN should be given with an amino acid level of 0.5 g/kg/d （other nutrients are provided accordingly）and BC volume should be reduced by 6.25 ml/kg/d. A detailed guideline for parenteral and enteral nutrition is described in an SOP: 'Parenteral and enteral nutrition SOP'.