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

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

3. 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

4. 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.

5. 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

6. 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

7. 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

9. Immunologic Function of the GI Tract:

10. 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.

11. 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.

12. 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

13. 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)

14. 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

15. 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

16. 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

17. 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):

18. 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):

19. 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

20. 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.

21. 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.

22. 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.

23. 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

24. 4 Major Actions of Lactoferrin That May Prevent NEC:
Sherman MP. Lactoferrin and Necrotizing Enterocolitis. Clin Perinatol. 2013; 40(1):

25. Sherman MP. Lactoferrin and Necrotizing Enterocolitis. Clin Perinatol

26. 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

27. 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

28. 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

29. Questions?

30. Thank you!

31. 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):
Sharma R, Hudak ML. A clinical perspective of necrotizing enterocolitis: past present and future. Clin Perinatol. 2013; 40:
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):
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 : 115(4):
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):
Richardson WM, et al. Nucleotide-binding oligomerization domain-2 inhibits toll-like receptor-4 signaling in the intestinal epithelium. Gastroenterology. 2010; 139(3):
Sodhi CP, et al. Toll-Like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in nectotizing enterocolitis. Gastroenterology. 2010; 138(1):
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):  

32. 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;
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:
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 ; 8(5):
American Academy of Pediatrics. AAP Reaffirms Breastfeeding Guidelines. press-room/pages/aap-reaffirms-breastfeeding-guidelines.aspx Published February 27, 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:
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:
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);
Herrmann K, Carroll, K. An exclusively Human Milk Diet Reduces Necrotizing Enterocolitis. Breastfeeding Med. 2014; 9(4):
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):
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.