Very Small Babies Benefit from Either Human or Cow-Based Milk Fortifiers

  • Premature babies with very low birth weights face many challenges to their survival and health.
  • Human milk alone does not adequately support the growth of very low-birth-weight babies.
  • A recent clinical trial suggests there is benefit to very low-birth-weight babies fed human milk supplemented with fortifiers based on either human or cow milk.

 

Life’s tough for very small premature babies. They face a daunting list of potential complications that could challenge their present and future health, and sometimes their survival [1-4]. Their families dread hearing the foreboding medical word “complication.” Babies weighing less than 1.5 kg (3 lb 4 oz) are classified by the World Health Organization as very low-birth-weight (VLBW) babies [5, 6]. To put that into perspective, the average birth weight in the USA is 3.3 kg (7 lb 4 oz) with 95% of babies ranging between a petite 2.5 kg (5 lb 8 oz) and the king or queen of the nursery at 5 kg (11 lb). Amazingly, many VLBW babies overcome their early life challenges with help from intensive neonatal medical care and go on to face the more important challenges within a child’s life, like learning to swim and passing grammar tests at school. One factor contributing to the health of VLBW babies is the use of milk-based nutritional fortifiers. But which fortifier is best?

Deborah O’Conner and twelve colleagues compared the supplementation of human milk with human milk-based fortifier or cow milk-based fortifier in a large group of VLBW babies [7]. This was the first clinical trial to investigate the relative merits of these fortifiers when added to mother’s milk topped up with donated human milk. The investigators are based in several Canadian institutions, although the extensive list of people in the acknowledgments highlights the broader North American scale of the investigation and its logistical complexity. The results of the investigation were recently published in the American Journal of Clinical Nutrition [7].

Very Low-Birth-Weight Babies Require Intensive Care

The main causes of very low birth weight in babies are premature birth and problems with the placenta, birth defects, or maternal health [8]. Some VLBW babies born prematurely have the expected maturity corresponding to their gestational age (time in pregnancy), others are not at their expected level of maturity. Thus, in addition to birth weight, doctors also rely on measures of baby development to assess the health risks of a VLBW baby and to tailor an intensive health-care treatment [9]. VLBW babies without early life complications often have remarkable “catch up” growth that eventually leads to a more normal growth pattern occurring in childhood [10]; resilience in biology is amazing. However, scientists report that these individuals may have greater risks of metabolic diseases, like obesity, but later in life [10].

For VLBW babies, it is all about putting on weight as soon as possible; time is not on their side. Scientists have demonstrated a strong correspondence between birth weight and the chance of survival [11]; the impersonal mortality-birth weight graph summarizing millions of births is precipitous and ominous. The survival rate of VLBW babies at one year of age in the U.S.A. in 2012 was about 100 fold less than normal birth weight babies [5], but this number is likely inflated somewhat by a population of extremely low-birth-weight babies unfortunately with very poor prospects. Increasing the weight of VLBW babies by intensive medical care and tailored nutrition helps them avoid complications and increases their survival chances.

Milk Fortifiers Make a Difference

Although mother’s milk is superbly formulated to meet the demands of the average baby, it alone is insufficient for the specific needs of a VLBW baby, which is often vulnerable to under-nutrition [7, 8]. Neonatal health-care specialists recommend that VLBW babies need additional nutritional support in the form of milk-based fortifiers to supplement mother’s milk or donated human milk [8]. The combined nutrition is typically fed through a tube directly into the stomach of the baby. Medical authorities now recommend that this approach to the feeding of VLBW babies is the best [7, 8]. Investigators involved in several older clinical trials demonstrated that human milk supplemented with a milk-based fortifier compared with human milk containing either no fortifier or supplementary formula milk increases growth of the VLBW baby and enhances its tolerance to the feeding tube [7, 12-15]. In addition, these investigators concluded that maternal milk containing fortifier reduces the risk of necrotizing enterocolitis (NEC), a life-threatening condition where parts of the bowel die for unknown reasons in premature babies [7, 12-15]. The investigators inferred that optimized growth of the VLBW baby may also decrease the risks of other complications.

The fortifiers are commercially-produced milk products containing concentrated milk protein and added carbohydrates, fats, calcium, trace minerals, and vitamins from various sources. Manufacturers of fortifiers often use protein components in cow’s milk due to its markedly lower cost and greater availability compared with donated human milk. Human milk-based fortifiers have only recently become available and have not been as extensively tested for benefits to babies compared with cow milk-based fortifiers [14, 15]. Health authorities usually make the assumption that the much more expensive human milk-based fortifiers must be better for VLBW babies than fortifiers made from cow’s milk. This assumption may lead to greater demand for the human product and a potential strain on the limited supply of donated human milk. However, this basic assumption has not been tested in a rigorous clinical trial, until recently.

A Clinical Trial Tells All

O’Conner and colleagues used a randomized and blind clinical trial to assess whether human milk-based fortifiers were better than cow milk-based fortifiers when administered to VLBW babies with mother’s milk topped up with human donor milk [7]. A randomized and blind trial is considered by scientists as the gold standard method to decide whether one clinical treatment is better than another. The investigators primarily measured babies’ growth, feeding tolerance, health complications, and gut inflammation. They also monitored the incidences of infection, NEC, lung disease, and eye damage. The investigators excluded babies from entering the trial if they had chromosomal or innate abnormalities affecting their growth or they did not meet specific feeding criteria. The exclusion of some babies was important so that informative results could be obtained from the trial. There were about 64 VLBW babies in each of two groups receiving mother’s milk topped up with donated and pasteurized human milk supplemented with either human or cow milk-based fortifiers. The average birth weight of all babies in the trial was a meager 888 grams (2 lb) and they were born on average about 10 weeks prematurely. The babies were randomly allocated to each treatment group to remove known and confounding biases from the analysis. The clinical trial was blinded, meaning that the staff administering the fortified milk did not know what treatment was being given to each baby during the trial, which continued from birth to 12 weeks of age. A few babies graduated early out of the trial because of their good general health.

When O’Conner and colleagues analyzed the extensive trial results they found no statistically significant differences between the two treatments for all the major baby measurements [7]. This is an important finding as the investigators concluded that VLBW babies can benefit from either the markedly less expensive and more widely available cow milk-based fortifier or the more expensive human milk-based fortifier. The use of the cow milk-based fortifier may reduce the strain on the limited supply of donated human milk. The investigators stated that they would need to follow-up on a slightly greater incidence of eye damage to some babies in the group receiving the cow milk-based fortifier.

Investigators who undertook related but different clinical trials in the past often concluded that a diet exclusively containing human milk and human fortifier is more helpful to VLBW babies than one using human milk supplemented with cow milk protein [16-18]. However, O’Conner and colleagues noted substantial differences in the designs of these clinical trials, their research aims, and the nature of the cow milk supplementation; they concluded that these other clinical trials were not comparable to their trial [7].

Implications

Medical authorities report that VLBW babies occur at a frequency of only about one in a hundred births, although the impact of these births within hospitals is very high [6, 8]. Milk fortifiers that improve VLBW baby growth and health may help free much-needed pediatric hospital space and expertise. Moreover, health workers can either use the widely available cow milk-based fortifiers or the more expensive human milk-based fortifiers and thereby help restrain the soaring costs of intensive care for VLBW babies.

VLBW babies are tiny, incredibly vulnerable, and often clinically unstable. Even using the best intensive medical care and the best nutritional supplementation in the clinical trial undertaken by O’Conner and colleagues, tragically a few babies died in both treatment groups and about half of the babies in both groups developed a major complication including infections, NEC, eye damage, and brain injury [7]. The risks of complications in both groups were presumably reduced by the nutritional fortifiers used in the trial, however the overall risk of adverse complications was still substantial. On the more positive side, many of the babies without complications in this trial will likely live a full and productive life, unlike what might have occurred if they had been born only a couple of decades ago. This is a remarkable story about how milk fortifiers and modern intensive medical care can change some lives for the better.

 

1. Hsiao CC, Tsai ML, Chen CC, Lin HC. Early optimal nutrition improves neurodevelopmental outcomes for very preterm infants. Nutr Rev. 2014;72(8):532-540.
2. Anderson AE, Wildin SR, Woodside M, Swank PR, Smith KE, Denson SE, et al. Severity of medical and neurologic complications as a determinant of neurodevelopmental outcome at 6 and 12 months in very low birth weight infants. J Child Neurol. 1996;11(3):215-219.
3. Miceli PJ, Goeke-Morey MC, Whitman TL, Kolberg KS, Miller-Loncar C, White RD. Brief report: birth status, medical complications, and social environment: individual differences in development of preterm, very low birth weight infants. J Pediatr Psychol. 2000;25(5):353-358.
4. Laffan EE, McNamara PJ, Amaral J, Whyte H, L’Herault J, Temple M, et al. Review of interventional procedures in the very low birth-weight infant (<1.5 kg): complications, lessons learned and current practice. Pediatr Radiol. 2009;39(8):781-790.
5. Martin JA, Hamilton BE, Osterman MJ, Curtin SC, Matthews TJ. Births: final data for 2012. Natl Vital Stat Rep. 2013;62(9):1-68.
6. World Health Organization. International statistical classification diseases and related health problems (ICD-10). Geneva: World Health Organization; 1992.
7. O’Connor DL, Kiss A, Tomlinson C, Bando N, Bayliss A, Campbell DM, et al. Nutrient enrichment of human milk with human and bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial. Am J Clin Nutr. 2018;108(1):108-116.
8. World Health Organization. Optimum feeding of low birth weight infants in low and middle income countries. Geneva; 2011.
9. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Measurement of fetal and infant maturity. In: Behrman R, Butler A, editors. Institute of Medicine (US) Committee on Understanding Premature Birth and Assuring Healthy Outcomes. Washington (DC): National Academies Press; 2007.
10. Raaijmakers A, Allegaert K. Catch-up growth in former preterm neonates: no time to waste. Nutrients. 2016;8(12).
11. Platt RW, Ananth CV, Kramer MS. Analysis of neonatal mortality:is standardizing for relative birth weight biased? BMC Pregnancy Childbirth. 2004;4(1):9.
12. Quigley M, McGuire W. Formula versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database Syst Rev. 2014(4):CD002971.
13. Ziegler EE. Human milk and human milk fortifiers. World Rev Nutr Diet. 2014;110:215-227.
14. Colaizy TT. Donor Human Milk for Very Low-Birth-Weight Infants. JAMA. 2016;316(18):1875-1876.
15. Colaizy TT. Donor human milk for very low birth weights: patterns of usage, outcomes, and unanswered questions. Curr Opin Pediatr. 2015;27(2):172-176.
16. Ghandehari H, Lee ML, Rechtman DJ, Group HMS. An exclusive human milk-based diet in extremely premature infants reduces the probability of remaining on total parenteral nutrition: a reanalysis of the data. BMC Res Notes. 2012;5:188.
17. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-Kohlendorfer U, et al. An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr. 2010;156(4):562-7.e1.
18. Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, et al. Randomized trial of exclusive human milk versus preterm formula diets in extremely premature infants. J Pediatr. 2013;163(6):1592-5.e1.

 

Contributed by
Dr. Ross Tellam (AM)
Research Scientist
Brisbane, Australia