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- Bovine colostrum for preterm babies

Babies born prematurely are extremely vulnerable as they have immature immune and gastrointestinal systems. The nature of the first nutrition is very important. Bovine colostrum is the best diet supplement to the mother’s own milk in preterm piglets used as models for preterm infants, and clinical trials on human infants are now started.

Preterms

Approximately 10 % of all infants are born prematurely (defined as before 37 weeks of gestation), and prematurity is the single most important direct cause of death in the critical first months of life (Blencowe et al., 2012). Some of the most obvious features about preterms are their low birth weight, immature gastrointestinal tract and impaired maturation of the immune system. This induces high risks of severe infections and long-term effects include reduced growth and impaired maturation of key organs, such as gut, brain and lungs (Howson et al., 2013).


Gastrointestinal development

The physical development of the gastrointestinal tract starts early after conception and is basically finished after 20 weeks of gestation, after which further development of movements and functions continues. At birth, the gastrointestinal tract is prepared for intake of oral feeding and to change accordingly in function and response. The final development and maturation of the gastrointestinal tract takes place after birth as a reaction to the new feeds and surrounding microflora. In the utero, the fetus ingest small amounts of the amniotic fluid around it. This fluid contains a broad range of bioactive factors that stimulate growth and development of the gastrointestinal tract. After birth, the colostrum from the mother is important for the continued maturation of the gut (Rasmussen, 2016).

The immature preterm gut

When a baby is born preterm, the process of gut maturation is interrupted before it has developed the functions to handle enteral nutrition. At the same time, mother’s own milk is often in limited supply or not available at all. Preterm infants thus have problems of getting the nutrients needed for further and final maturation and development of the gastrointestinal tracts. Therefore, the first nutrition of premature infants is a major challenge in neonatal intensive care units worldwide, and intravenous feeding is often the only option. However, for the final development of the gut enteral feeding is necessary (Hawson et al., 2013).

Necrotizing enterocolitis

Necrotizing enterocolitis (NEC) is a life-threatening, but common, complication in preterm infants that causes severe ulceration of the small and large gut. It is characterized by inflammation and necrosis of the intestine which may lead to perforation, infection and death. The etiology of the disease is unknown, but pro-inflammatory molecules and the nature of the first enteral nutrition are thought to be involved. The mortality rate range from 20-30%, with the highest rate among infants requiring surgery. The extensive inflammation in the intestines may affect distant organs, such as the brain, which place affected infants at high risk of neurodevelopmental delays. Due to the devastating and widespread nature of this disease, and the difficulties of eradicating it, the search for a cure has been a strong priority in pediatric medicine (Neu & Walker, 2011). Nutrition is considered important in the prevention and management of necrotizing enterocolitis (Fallon et al., 2012).

Importance of the first nutrition for premature babies

Most premature babies demonstrate a weight loss or a stagnating growth curve the first weeks of life. Recent research suggests that this lack of growth may be related to a generally slower growth rate and a delayed maturation of the brain. Consequently, there is a need for a “first nutrition” for pre-term babies that is well tolerated by the infant and will help mature the gut (Hawson et al., 2013).


Mother’s milk is the best

As all other mammals, the very first milk provided by the mother is the colostrum, and it provides the newborn baby with the optimal amounts of essential nutrients and bioactive factors needed to get the best possible start of life. Thus, mothers own milk is recognized as the optimal diet for the infant and national standards for infant nutrition recommends breastfeeding as the first oral nutrition for infants (Johnston et al., 2012; Nilsson et al., 2013).


The perfect start

Colostrum has evolved to contain the specific compounds in the precise amounts needed by the infant to get the very best start of life. The content of human colostrum matches the needs of the baby, just as the content of bovine colostrum matches that of the newborn calf. For babies this includes immunoglobulins to finish the maturation of the immune system, antibacterial factors to prevent colonization from harmful bacteria and pathogens, growth factors to help develop the fully functional gut, vitamins, minerals, carbohydrates, lipids, proteins and much more (Rathe et al., 2014).

Important contents in human colostrum

The immune components in colostrum is important for all mammalian newborns, but colostrum is also an important source of protective and nutritional factors and growth hormones for the baby (Palmer et al., 2006). It also contains a much higher variation and mixture of a variety of up to 100 different oligosaccharides (Urashima et al., 2001).


Diet supplements for preterms

But as mother’s milk is the optimal diet for the newborn and preterm babies, the supply is often limited or even absent in preterm births, diet supplements are needed. Human donor milk is often regarded as the second best choice of food for preterm infants, but it consist of mature milk from later in lactation and do not contain the large amounts of bioactive compounds found in colostrum. Many recommendations for infant feeding focus mainly on the nutritional values of the diet and infant formulas are produced and constantly optimized to match the nutritional values and chemical composition of human milk (Macy, 1949). Infant formula is the choice in clinic’s with no access to human donor milk, although feeding infant formulas delays intestinal maturation and increase the risk of necrotizing enterocolitis (Shen et al., 2015). Many clinic use infant formula, which is fabricated to meet the nutritional needs of the baby, but is often completely lacking the important milk matrix and the high amounts of bioactive compounds found in colostrum. Infant formula has also been found to induce necrotizing enterocolitis (Møller et al., 2011; Støy et al., 2014; Shen et al., 2016)

Bovine colostrum proved to be best diet supplement for preterms

Bovine colostrum contains very high amounts of the same bioactive compounds found in human colostrum. It has been has proven that providing colostrum as part of the initial diet improved gut maturation and reduced the risk of infection in preterm piglets (Møller et al., 2011). Several studies from the project NEOMUNE also report colostrum to have gut protective effects in premature piglets suffering from the same gastrointestinal challenges as the premature baby. It was found to be superior to both human donor milk and infant formula (Li et al., 2014; Rathe et al., 2014; Shen et al., 2015). These results have provided a strong hope that bovine colostrum may be the needed agent against necrotizing enterocolitis in preterm infants (Jensen et al., 2013; Li et al., 2014; Støy et al., 2014; Shen et al., 2015). Bovine colostrum is now tested in a safety and feasibility study in preterm infants (ClinicalTrials.gov NCT02054091) and further large scale tests are prepared in hospitals in Denmark and China, where bovine colostrum will be used as a fortifier for mother’s milk and donor milk for preterm children with very low birth weight. These clincal studies are parts of the project NEOCOL that focus on developing a bovine colostrum based diet supplement for preterm infants.


References

Blencowe, H., Cousens, S., Østergaard, M. Z., Chou, D., Moller, A.-B., Narwal, R., Adler, A., Garcia, C. V., Rohde, S., Say, L. & Lawn, J. E. (2012) National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet, 379 (9832), 2167-2172.

Hawson, C. P., Kinney, M. V., McDougall, L. & Lawn, J. E., on the behalf of the Born Too Soon Preterm Birth Action Group (2013) Born too soon: preterm birth matters. Reproductive Health, 10(Suppl. 1), S1-S10.

Jensen, M. L., Sangild, P. T., Lykke, M., Schmidt, M., Boye, M., Jensen, B. J. & Thymann, T. (2013) Similar efficiacy of human banked milk and bovine colostrum to decrease incidence of necrotizing enterocolitis in preterm piglets. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology, 305(1), R4-R12.

Johnston, M., Landers, S., Noble, L., Szucs, K. & Viehmann, L. (2012) Breastfeeding and the use of human milk. Pediatrics: Section of breastfeeding, 129(3), e827-841.

Li, Y., Jensen, M. L., Chatterton, D. E. W., Jensen, B. J., Thymann, T., Kvistgaard, A. S. & Sanild, P. T. (2014) Raw bovine milk improves gut responses to feeding relative to infant formula in preterm piglets. American Journal of Physiology – Gastrointestinal and Liver Physiology, 306(1), G81-G90.

Macy, I. G. (1949) Composition of human colostrum and milk. American Journal of Diseases of Children, 78(4), 589-603.

Møller, H. K., Thymann, T., Fink, L. N., Frokiaer, H., Kvistgaard, A. S. & Sangild, P. T. (2011) Bovine colostrum is superior to enriched formulas in stimulating intestinal function and necrotising enterocolitis resistance in preterm pigs. British Journal of Nutrition, 105, 44-53.

Neu, L. & Walker, W. A. (2011) Necrotizing enterocolitis. The New England Journal of Medicine, 364(3), 255-264. Nilsson, I., Aaskov, M., Schack-Nielsen, L., Jerris, T., m.fl. (2013) Amning – en håndbog for sundhedspersonale. Sundhedsstyrelsen. 3. udgave, 1. oplag.

Rasmussen, S. O. (2016) Tarmens udvikling fra undfangelse til fødsel. Biodane Pharma, 1. ed.

Rathe, M., Müller, K., Sangild, P. T. & Husby, S. (2014) Clinical applications of bovine colostrum therapy: a systematic review. Nutrition Reviews, 72(4), 237-254.

Shen, R. L., Thymann, T., Østergaard, M. V., Støy, A. C. F., Krych, Ł., Nielsen, D. S., Lauridsen, C., Harmann, B., Holst, J. J., Burrin, D. G & Sangild, P. T. (2015) Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs. American Journal of Physiology – Gastrointestinal and Liver Physiology, 309, G310-G323.

Shen, R. L., Pontoppidan, P. E., Rathe, M., Hansen, C. F., Buddington, R. K., Heegaard, P. M. & Sangild, P. T. (2016) Milk diets influence doxorubicin-induced intestinal toxicity in piglets. American Journal of Physiology – Gastrointestinal and Liver Physiology, 311(2), G324-333.

Støy, A. C. F., Østergaard, M. V. & Sangild, P. T. (2014) Amniotic fluid and colostrum as potential diets in the critical care of preterm infants. Diet and Nutrition in Clinical Care, 6-14.

Urashima, T., Saito, T., Nakamura, T. & Messer, M. (2001) Oligosaccharides of milk and colostrum in non-human mammals. Glycoconjugate Journal, 18(5), 357-371.
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