Delayed Initiation but Not Gradual Advancement of Enteral Formula Feeding Reduces the Incidence of Necrotizing Enterocolitis (NEC) in Preterm Pigs

Ghoneim, Nada; Bauchart-Thevret, Caroline; Oosterloo, Berthe C; Stoll, Barbara J.; Kulkarni, Madhulika; Pipaón, Miguel Sáenz de; Zamora, Irving J.; Olutoye, Oluyinka O.; Berg, Brian M.; Wittke, Anja; Burrin, Douglas G.

doi:10.1371/journal.pone.0106888

Cited by 29 publications

(28 citation statements)

References 38 publications

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“…Regardless, the middle and distal small intestine is consistently affected when NEC progresses to more severe stages in preterm pigs (7). Our results are consistent with another recent study in preterm pigs showing that early gradual advancement of enteral formula induces NEC and that delayed formula introduction (until after day 5) decreases NEC incidence (23). The "subclinical NEC phenotype" in our study may be similar to the clinical situation in many preterm infants, where early diagnosis is difficult and limited to X-rays or noninvasive means such as increased gastric residuals (i.e., feeding intolerance).…”

Section: Discussionsupporting

confidence: 92%

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Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs

Shen

Thymann

Østergaard

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Shen RL, Thymann T, Østergaard MV, Støy AC, Krych Ł, Nielsen DS, Lauridsen C, Hartmann B, Holst JJ, Burrin DG, Sangild PT. Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs. Am J Physiol Gastrointest Liver Physiol 309: G310 -G323, 2015. First published July 2, 2015; doi:10.1152/ajpgi.00163.2015.-It is unclear when and how to start enteral feeding for preterm infants when mother's milk is not available. We hypothesized that early and slow advancement with either formula or bovine colostrum stimulates gut maturation and prevents necrotizing enterocolitis (NEC) in preterm pigs, used as models for preterm infants. Pigs were given either total parenteral nutrition (TPN, n ϭ 14) or slowly advancing volumes (16 -64 ml·kg Ϫ1 ·day Ϫ1 ) of preterm infant formula (IF, n ϭ 15) or bovine colostrum (BC, n ϭ 13), both given as adjunct to parenteral nutrition. On day 5, both enteral diets increased intestinal mass (27 Ϯ 1 vs. 22 Ϯ 1 g/kg) and glucagon-like peptide 2 release, relative to TPN (P Ͻ 0.05). The incidence of mild NEC lesions was higher in IF than BC and TPN pigs (60 vs. 0 and 15%, respectively, P Ͻ 0.05). Only the IF pigs showed reduced gastric emptying and gastric inhibitory polypeptide release, and increased tissue proinflammatory cytokine levels (IL-1␤ and IL-8, P Ͻ 0.05) and expression of immunerelated genes (AOAH, LBP, CXCL10, TLR2), relative to TPN. The IF pigs also showed reduced intestinal villus-to-crypt ratio, lactose digestion, and some plasma amino acids (Arg, Cit, Gln, Tyr, Val), and higher intestinal permeability, compared with BC pigs (all P Ͻ 0.05). Colonic microbiota analyses showed limited differences among groups. Early feeding with formula induces intestinal dysfunction whereas bovine colostrum supports gut maturation when mother's milk is absent during the first week after preterm birth. A dietdependent feeding guideline may be required for newborn preterm infants.

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Section: Discussionsupporting

confidence: 92%

“…Previous studies in both preterm pigs and infants have shown that rapid advancement of feeding with infant formula induces NEC (6,15,23). This supports the general practice to initially feed very small volumes before advancing feedings gradually.…”

supporting

confidence: 68%

Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs

Shen

Thymann

Østergaard

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…The incidence of NEC across developed countries is ;5-12% for VLBW infants (13)(14)(15)(16)(17)(18), depending on certain risk factors. Three major risk factors for NEC are <32 wk gestational age, <1500 g at birth, and cardiac complications (10).…”

Section: Necmentioning

confidence: 99%

“…Last, there are distinct differences between term and preterm infants in regard to the expression of immune cells and signaling pathways. A preterm immune system cannot readily detect pathogens and protect against infections due to multiple associated factors such as 1) the decreased production of IgA, IgM, IgG, and defensins; 2) changes in the expression of toll-like receptors (TLRs), especially TLR4 and TLR9, which are involved in pathogen recognition and the activation of the innate immune system (14,28,29); and 3) upregulation of proinflammatory TLRs (26) and/or proinflammatory cytokines such as TNF-a, IL-6, IL-8, and IL-1b (26,27). The culmination of these factors increases a preterm infant's vulnerability to infections and disease, particularly NEC.…”

Section: Necmentioning

confidence: 99%

Current Knowledge of Necrotizing Enterocolitis in Preterm Infants and the Impact of Different Types of Enteral Nutrition Products

Shulhan¹,

Dicken²,

Hartling³

et al. 2017

Advances in Nutrition

104

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Preterm infants are extremely vulnerable to a range of morbidities and mortality. Underdeveloped cardiac, respiratory, gastrointestinal, and immune systems in the preterm period increase the risk of necrotizing enterocolitis (NEC), a serious disease of the gut. NEC affects 5-12% of very-low birthweight infants, leads to surgery in 20-40% of cases, and is fatal in 25-50% of cases. There are multiple factors that may contribute to NEC, but the exact cause is not yet fully understood. Severe cases can result in intestinal resection or death, and the health care costs average >$300,000/infant when surgical management is required. Different types of nutrition may affect the onset or progression of NEC. Several studies have indicated that bovine milk-based infant formulas lead to a higher incidence of NEC in preterm infants than does human milk (HM). However, it is not clear why HM is linked to a lower incidence of NEC or why some infants fed an exclusively HM diet still develop NEC. An area that has not been thoroughly explored is the use of semielemental or elemental formulas. These specialty formulas are easy to digest and absorb in the gut and may be an effective nutritional intervention for reducing the risk of NEC. This review summarizes what is known about the factors that contribute to the onset and progression of NEC, discusses its health care cost implications, and explores the impact that different formulas and HM have on this disease. Adv Nutr 2017;8:80-91.

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“…Early GI maturation may help to prevent later adverse effects of slow growth and inadequate nutrient intake in preterm infants (30). On the other hand, too rapid advancement of enteral feeding is associated with high NEC risk, and delayed advancement of enteral feeding may decrease NEC risk in both preterm infants and pigs (20,32,33). Consequently, a gradual introduction of mother's own milk, donor milk, or infant formula ("minimal enteral nutrition," daily increases of 10 -20 ml·kg Ϫ1 ·day Ϫ1 ), is often used for 1-2 wk after birth as adjunct to parenteral nutrition (PN), before transition to full enteral feeding at 2-4 wk (e.g., 150 -180 ml·kg Ϫ1 ·day Ϫ1 ).…”

mentioning

confidence: 99%

Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs

Hansen

Thymann

Andersen

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Preterm infants often tolerate full enteral nutrition a few weeks after birth but it is not known how this is related to gut maturation. Using pigs as models, we hypothesized that intestinal structure and digestive function are similar in preterm and term individuals at 3-4 wk after birth and that early enteral nutrition promotes maturation. Preterm or term cesareandelivered pigs were fed total parenteral nutrition, or partial enteral nutrition [Enteral (Ent), 16 -64 ml·kg Ϫ1 ·day Ϫ1 of bovine colostrum] for 5 days, followed by full enteral milk feeding until day 26. The intestine was collected for histological and biochemical analyses at days 0, 5, and 26 (n ϭ 8 -12 in each of 10 treatment groups). Intestinal weight (relative to body weight) was reduced in preterm pigs at 0 -5 days but ENT feeding stimulated the mucosal volume and peptidase activities. Relative to term pigs, mucosal volume remained reduced in preterm pigs until 26 days although plasma glucagon-like peptide 2 (GLP-2) and glucose-dependent insulin-trophic peptide (GIP) levels were increased. Preterm pigs also showed reduced hexose absorptive capacity and brush-border enzyme (sucrase, maltase) activities at 26 days, relative to term pigs. Intestinal structure shows a remarkable growth adaptation in the first week after preterm birth, especially with enteral nutrition, whereas some digestive functions remain immature until at least 3-4 wk. It is important to identify feeding regimens that stimulate intestinal maturation in the postnatal period of preterm infants because some intestinal functions may show long-term developmental delay. prematurity; gut development; enzymes; digestion; glucagon-like peptide 2 ABOUT 10% OF ALL INFANTS are born preterm (Ͻ37 weeks of gestation) and the proportion is increasing in most countries (6). Preterm infants show an increased susceptibility to infections, respiratory distress syndrome, intracranial hemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity, extrauterine growth restriction, neurodevelopmental disturbances, and necrotizing enterocolitis (NEC) (21, 31). The challenges are inversely related to gestational age at birth and the most severe adaptation problems occur during the first few weeks after birth. If preterm infants survive the difficult neonatal period, their body functions often adapt well, although some organ systems may show long-term developmental delay or deficits (18). It remains unknown how different organ systems adapt in preterm infants and when parameters of structure and function become similar to those in term infants. For gastrointestinal (GI) functions, eating disorders and dysregulated appetite have been reported in preterm infants (44) but very little is known about the long-term adaptation of the GI tract in preterm neonates.Investigations of postnatal GI adaptation in preterm neonates are difficult without an animal model that combines preterm birth, high NEC risk, and clinically relevant feeding interventions, such as parenteral and enteral nutrition. Piglets delivere...

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Delayed Initiation but Not Gradual Advancement of Enteral Formula Feeding Reduces the Incidence of Necrotizing Enterocolitis (NEC) in Preterm Pigs

Cited by 29 publications

References 38 publications

Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs

Early gradual feeding with bovine colostrum improves gut function and NEC resistance relative to infant formula in preterm pigs

Current Knowledge of Necrotizing Enterocolitis in Preterm Infants and the Impact of Different Types of Enteral Nutrition Products

Rapid gut growth but persistent delay in digestive function in the postnatal period of preterm pigs

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