Necrotizing Enterocolitis: Pathophysiology, Risk Factors, & Prevention Presented by: Holly Murphy, IBCLC 2017-18 Sodexo Dietetic Intern, Allentown campus April 26, 2018

Overview: What is necrotizing Enterocolitis (NEC)? Epidemiology Pathogenesis Presentation & Management Risk Factors Prevention of Onset

Learning Objectives: 1. Participants will be able to define necrotizing enterocolitis (NEC) 2. Participants will be able to list 3 elements believed to play a role in NECs etiology 3. Participants will be able to list 2 best-practice methods in the prevention of NECs onset in high risk neonates

Necrotizing Enterocolitis (NEC) The most common GI emergency found in the NICU1 Predominantly affects preterm (<37 weeks) and VLBW infants (500g-1,500g) in the first 1 to 3 weeks of life1 High rates of morbidity and mortality Approx 1,500-2,000 newborns die each year in the US alone Unknown etiology Characterized by: Acute inflammation and infection of the bowel Decreased perfusion resulting in damage to the GI tract: Mucosal injury Full-thickness necrosis and perforation Spillage of stool into the infant’s abdominal cavity Necrotizing enterocolitis is a devastating illness that affects mostly preterm infants in the second or third week of life, and has high rates of morbidity and mortality. The actual cause remains unknown. NEC occurs when the lining of the intestines becomes inflamed, is sloughed off and then dies. Decreased blood flow to the gut, use of formula, a possible bacterial infection and a compromised immune system are all possible contributing causes. In severe cases there will be perforation of the intestines, and the infant will require surgery to remove the necrotic tissue and to prevent death, although mortality rates are high. Back in 1990 Alan Lucas studied preterm infants in a multicenter trial and found that infants fed exclusively formula had 10x the rate of NEC compared to exclusive breastfeeding, and infants fed partial breast milk and partial formula had 3x greater risk compared to exclusive breastfeeding. More recent studies have looked at an all human milk diet, including fortifiers made from human milk, and they found a 50% reduction in medical NEC and a 90% reduction in surgical NEC compared to infants fed human milk with cow’s milk fortifiers which is standard practice.

Epidemiology: Approximately 85-90% of cases occur in preterm (32-37 weeks gestation) or very preterm infants (28-32 weeks) About 10% of VLBW infants will develop NEC Mortality estimated at up to 40% of those affected Highest rates with those requiring surgical intervention

Pathogenesis: Clinical presentation can widely vary Early signs are so non-specific that a conclusive diagnosis cannot be made Bell’s Staging Criteria developed to aid in dx and management of NEC Severity of presentation categorized based on clinical, radiographic, and laboratory criteria Treatment guidelines are provided

Bell’s Staging Criteria Stage Clinical X-Ray Treatment I. Suspected NEC Mild abd. distension Poor feeding tolerance Temp instability Lethargy Apnea Bradycardia Emesis Mild abdominal distension with mild ileus Evaluation of electrolyte status & coagulation studies Rule out: Sepsis, gastroenteritis, hypoglycemia… D/C enteral feeds IV antibiotics II. Confirmed NEC Significant abdominal distention GI bleed Significant abdominal distention with ileus Small bowel separation with edema in bowel wall or peritoneal fluid Persistent rigid bowel loops Pneumatosis intenstinalis Portal vein gas Decompression of the bowel Initiation of systemic systemic broad spectrum antibiotic therapy III. Advanced NEC Septic shock Metabolic acidosis May progress to bowel perforation Pneumoperitoneum secondary to perforation Surgical intervention

https://www.chla.org/necrotizing-enterocolitis

Immunologic Function of the GI Tract: https://www.intechopen.com/books/preterm-birth/microbes-and-the-inflammatory-response-in-necrotising-enterocolitis

Timeline of GI Development: -Let’s take a look at the timeline of GI development in utero. -The gastrointestinal tract is one of the first structures that develop in the growing embryo -Intestinal villa and other cellular components develop in the first trimester along with secretion of digestive enzymes -Gut motility first appears around 23 weeks and becomes progressively more organized by 28 weeks. It’s important to start small volume feeds with breast milk early to prime the gut. Premature infants have delayed gastric emptying that improves with exposure to human milk and with small volume feeds. Formula slows down gastric emptying. Necrotizing enterocolitis is a devastating illness that affects mostly preterm infants in the second or third week of life, and has high rates of morbidity and mortality. The actual cause remains unknown. NEC occurs when the lining of the intestines becomes inflamed, is sloughed off and then dies. Decreased blood flow to the gut, use of formula, a possible bacterial infection and a compromised immune system are all possible contributing causes. In severe cases there will be perforation of the intestines, and the infant will require surgery to remove the necrotic tissue and to prevent death, although mortality rates are high. Back in 1990 Alan Lucas studied preterm infants in a multicenter trial and found that infants fed exclusively formula had 10x the rate of NEC compared to exclusive breastfeeding, and infants fed partial breast milk and partial formula had 3x greater risk compared to exclusive breastfeeding. More recent studies have looked at an all human milk diet, including fortifiers made from human milk, and they found a 50% reduction in medical NEC and a 90% reduction in surgical NEC compared to infants fed human milk with cow’s milk fortifiers which is standard practice.

Risk factors predisposing the premature gut to NEC: Neu J, Weiss MD. Weiss. Necrotizing Enterocolitis: Pathophysiology and Prevention. Journal of Parenteral and Enteral Nutrition. 1999; 23(5): S13-S17.

Lipopolysaccharide receptor Toll-like receptor 4 (TLR4) TLR4 is a microbial recognition receptor located on the intestinal epithelium Activated by the body’s pro-inflammatory response Result: enterocyte apoptosis impaired mucosal healing Impaired perfusion Necrosis A recent randomized controlled study into NECs development in mice found that TLR4 is fundamental in the development of NEC. Mice with enterocyte-specific deletion of TLR4 were immune to NECs development Similar protection in wild-type mice receiving novel TLR4 receptor inhibitor

Lipopolysaccharide receptor Toll-like receptor 4 (TLR4) Epidermal Growth Factor (EGF) Abundantly found in human amniotic fluid and human breast milk Known to be an integral factor in intestinal development Laboratory studies have found that both amniotic fluid and human breast milk inhibit TLR4 signaling via Epidermal Growth Factor Receptor (EFGR)

Prevention of Onset No known method to ensure prevention of NEC Studies have repeatedly shown a significantly reduced incidence of NEC and related mortality in infants fed an exclusively human milk diet. The American Academy of Pediatrics recommends: Exclusively human milk diet for the first 6 months of life Continued breastfeeding as complimentary foods are introduced throughout the first year of life and beyond, as mutually desired by both baby and mother

Prevention of Onset Multicenter, randomized, controlled study Compared infant diets exclusive to human milk to those supplemented with preterm formula and/or bovine based fortifiers Results: Overall 77% reduction in probability of developing NEC in VLBW infants 50% reduction in medical NEC 90% reduction in surgical NEC

Human Milk Fortifiers Preterm and VLBW infants have increased nutritional requirements Greater than what human milk alone provides Fortifiers often added to human milk or formula to help meet these needs Historically bovine-based Human-milk based fortifiers have recently become available Infants supplemented with human milk-based fortifiers vs bovine-based Significant reduced incidence of NEC, mortality Significantly earlier postmenstrural age (gestational age plus chronological age) at discharge Decreased hospital length of stay Improved feeding tolerance

Distribution of Cases of NEC by Gestational Age: Bovine-based diet vs Exclusively Human Milk Diet Hair, AB., et al. Beyond necrotizing enterocolitis prevention: Improving outcomes with an exclusive human milk–based diet. Breastfeeding Medicine. 2016; 11(2): 70-74.

NEC and Mortality Rates: Bovine based vs. Exclusively Human Milk diet Hair, AB., et al. Beyond necrotizing enterocolitis prevention: Improving outcomes with an exclusive human milk–based diet. Breastfeeding Medicine. 2016; 11(2): 70-74.

Exclusively Human Milk-Based Diets in VLBW Infants Assad et al completed a retrospective chart review study: Results showed an exclusively pasteurized, banked human milk diet in VLBW infants: Significantly reduced incidence of NEC Best tolerated diet Significantly reduced hospital length of stay Significantly reduced total cost of hospitalization

Assad M, Elliott MJ, Abraham JH Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. Journal of Perinatology. 2015; 1-5.

Assad M, Elliott MJ, Abraham JH Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. Journal of Perinatology. 2015; 1-5.

Assad M, Elliott MJ, Abraham JH Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. Journal of Perinatology. 2015; 1-5.

Lactoferrin (LF) Supplementation LF supplementation is emerging as a promising new potential method of NEC prevention Part of the transferrin family of iron-binding glycoproteins Involved in iron homeostasis and antimicrobial defense against infection Naturally found in human milk 7g/L in colostrum 1g/L in mature human milk Form of natural “added protection” provided to newborns in the first several days of life

4 Major Actions of Lactoferrin That May Prevent NEC: Sherman MP. Lactoferrin and Necrotizing Enterocolitis. Clin Perinatol. 2013; 40(1): 79-91.

Sherman MP. Lactoferrin and Necrotizing Enterocolitis. Clin Perinatol

Conclusions: NEC is a common and potentially fatal GI emergency occuring in the NICU NECs etiology is not well understood Presentation can vary widely An exclusively human milk-based diet has been shown to significantly reduce the incidence of NEC Lactoferrin supplementation is emerging as a potential new method of preventing NEC in high risk neonates

Directions For Future Research More research is needed to further define NECs etiology Research into human milk and its antimicrobial and anti-inflammatory properties may hold the answer to the future prevention of NEC Lactoferrin Bovine vs Human Milk

Potential Conflict of Interest Prolacta Bioscience The leading for-profit manufacturer of human milk derived products for NICUs, including human milk based fortifiers Provides grants/funding for much of the current research into exclusively human milk based diets

Questions?

Thank you!

References: Adamkin, DH. Mother’s Milk, Feeding Strategies, and Lactoferrin to prevent Necrotizing Enterocolitis. Journal of Parenteral and Enteral Nutrition. 2012; 36(S1): 25S-29S. Hair, AB., et al. Beyond necrotizing enterocolitis prevention: Improving outcomes with an exclusive human milk–based diet. Breastfeeding Medicine. 2016; 11(2): 70-74. Sharma R, Hudak ML. A clinical perspective of necrotizing enterocolitis: past present and future. Clin Perinatol. 2013; 40:27- 51. Neu J, Weiss MD. Weiss. Necrotizing Enterocolitis: Pathophysiology and Prevention. Journal of Parenteral and Enteral Nutrition. 1999; 23(5): S13-S17. Huda S, Chaudhery S, Ibrahim H, et al. Neonatal necrotizing enterocolitis: clinical challenges, pathophysiology and management. Pathophysiology. 2014: 21:3-12. Dominguez, JA. Use of Minimal Enteral Nutrition to Prevent Necrotizing Enterocolitis: Got Milk? Journal of Parenteral and Enteral Nutrition. 2011; 35(1): 14-15. Bell MJ, Ternberg JL, Feigin RD, et al. Neonatal Necrotizing Enterocolitis. Therapeutic Decisions Based Upon Clinical Staging. Ann Surg. 1978; 187(1): 1-7. Berseth CL. Gestational evolution of small intestine motility in preterm and term infants. The Journal of pediatrics. 1989: 115(4): 646-651. Rayyis, Suha F, et al. Randomized trial of “slow” versus “fast” feed advancements on the incidence of necrotizing enterocolitis in very low birth weight infants. The Journal of pediatrics. 1999; 134(3): 293-297. Richardson WM, et al. Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology. 2010; 139(3): 904-917. Sodhi CP, et al. Toll-Like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in nectotizing enterocolitis. Gastroenterology. 2010; 138(1): 185-196. Yazki I, et al. Endothelial TLR4 activation impairs intestinal microcirculatory perfusion in necrotizing enterocolitis via eNOS-NO- nitrate signaling. Proceedings of the National Academy of Sciences on the USA. 2013; 110(23): 9451-9456. 

References: Sodhi CP, et al. Intestinal epithelial toll-like receptor 4 regulates goblet cell development and is required for necrotizing enterocolitis in mice. Gastroenterology. 2012; 143; 708-718. Neal MD, et al. Discovery and validation of a new class of small molecule Toll-like receptor 4 (TLR4) inhibitors. PLoS One. 2013; 8(6): e65779. Good M, et al. Amniotic Fluid inhibits Toll-like receptor 4 signaling in the fetal and neonatal intestinal epithelium. Proc. Natl. Acad. Sci USA. 2012; 109: 11330-11335. Good M, Sodhi CP, Egan CE, et al. Breast milk protects against the development of necrotizing enterocolitis through inhibition of Toll-like receptor 4 in the intestinal epithelium via activation of the epidermal growth factor receptor. Mucosal immunology. 2015; 8(5): 1166-1179. American Academy of Pediatrics. AAP Reaffirms Breastfeeding Guidelines. https://www.aap.org/en-us/about-the-aap/aap- press-room/pages/aap-reaffirms-breastfeeding-guidelines.aspx Published February 27, 2012. Accessed March 31, 2018. Schandler, RJ, et al. Randomized trial of donor human milk versus preterm formula as substitutes for mothers’ own milk in the feeding of extremely premature infants. Pediatrics. 2005; 116: 400-406. Sullivan S, 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: 562-567. Cristofalo EA, Schanler RJ, Blanco CL, et al. Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants. The Journal of pediatrics. 2013; 163(6);1592-1595. Herrmann K, Carroll, K. An exclusively Human Milk Diet Reduces Necrotizing Enterocolitis. Breastfeeding Med. 2014; 9(4): 184- 190. Assad M, Elliott MJ, Abraham JH. Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet. Journal of Perinatology. 2015; 1-5. Hair AB, et al. Premature Infants 750-1,250 g Birth Weight Supplemented with a Novel Human Milk Derived Cream Are Discharged Sooner. Breastfeeding Medicine. 2016; 11(3): 133-137. Manzoni P, et al. Bovine lactoferrin supplementation for prevention of necrotizing enterocolitis in very-low-birth-weight neonates: a randomized clinical trial. Early Hum Dev. 2014; 90 (Suppl 1): S60-65.