Written by Alexander Penn, PhD

Necrotizing enterocolitis (NEC) is a multifactorial disease, that’s not completely understood. NEC is likely caused by a variety of factors, and often, it is likely that more than one factor must be present for NEC to occur.

The most common risk factor of NEC is prematurity, which confers susceptibility to the disorder. Another common risk factor is an abundance of pathogenic bacteria in the intestine. One of the only protective factors that we agree on is the use of human milk, especially mother’s own milk, over formula. It makes sense that mother’s milk should reduce the incidence of NEC, since it helps to mature the premature intestine and has numerous factors in it that fight pathogenic bacteria, while encouraging the growth of helpful bacteria. Unfortunately, when NEC occurs despite use of human milk or even mother’s own milk, this can leave everyone wondering what went wrong. It suggests that a causative factor has been overlooked. 

Alexander Penn, PhD

I have proposed a causative factor paired with a protective factor in milk [1]. The causative factor is the release of large quantities of fatty acids as dietary fat is digested. Fatty acids are detergents capable of causing intestinal cell death (i.e. necrosis), which could initiate or contribute to the development of NEC [2]. Fatty acids do not normally cause issues in children and adults because of protections in the mature intestine (e.g. the layer of mucus covering the interior surface of the intestine) that are lacking in immature intestine. Since infants, especially premature infants, may be unable to produce sufficient mucus to protect from fatty acids, milk has evolved protections. Fat digestion is restrained in milk so that fatty acids are produced at a slower rate than in formula [2].

Additionally, there is a protein in milk (sometimes, but not always present in infant formula) that, as it is digested, is able to bind to fatty acids, making them harmless [2]. I have come across two ways that this protection might fail, however. First, the amount of fatty acids may overwhelm the amount of protein. This can happen when human milk is refrigerated for more than a couple of days or frozen for more than a couple of months. Enzymes in the milk break down the fat during storage, releasing a large amount of fatty acids, effectively giving them a head start on the protein, which is not broken down until it is ingested [3]. This could be a potential issue with donor human used in neonatal intensive care units, since donor milk is often stored for three months by donors before batch shipping to milk banks (please note that donor milk is still less harmful than formula and contains many other beneficial factors lacking in formula). The other way this protection might fail is if the protein is not digested properly in the intestine into its protective form. This could occur when the pancreas is not producing sufficient amounts of protein-digesting enzymes (i.e. pancreatic insufficiency). This may be more likely in infants that are premature and/or small for gestational age [4]. It is worth mentioning that in that study of pancreatic function in 21 premature infants, two infants developed NEC. Both were fed mother’s milk and both consistently had undetectable levels of fecal chymotrypsin (an enzyme that digests protein).

In my opinion, when NEC is suspected in infants that have received only human milk, we should be testing their milk supply for presence of excessive fatty acids (or at least asking how long it was stored) and testing their fecal samples for pancreatic insufficiency. A study along those lines could potentially lead to preventative measures that could go a long way towards reducing NEC rates to zero.

References

1. Penn A. Cytotoxicity from digested formula and how it may contribute to necrotizing enterocolitis. In: Preedy V, ed. Handbook of dietary and nutritional aspects of bottle feeding. Wageningen: Wageningen Academic Publishers; 2014, pp 587-606.
2. Penn AH, Altshuler AE, Small JW, Taylor SF, Dobkins KR, Schmid-Schönbein GW: Digested formula but not digested fresh human milk causes death of intestinal cells in vitro: implications for necrotizing enterocolitis. Pediatric Research 72(6):560-567, 2012.
3. Penn AH, Altshuler AE, Small JW, Taylor SF, Dobkins KR, Schmid-Schonbein GW: Effect of digestion and storage of human milk on free fatty acid concentration and cytotoxicity. J Pediatr Gastroenterol Nutr 59(3):365-373, 2014.
4. Kolacek S, Puntis JW, Lloyd DR, Brown GA, Booth IW: Ontogeny of pancreatic exocrine function. Arch Dis Child 65(2):178-181, 1990.