Necrotizing Enterocolitis What Do We Know What Can

Necrotizing Enterocolitis: What Do We Know? What Can We Do? Terry S. Johnson, APN, NNP-BC, CLEC, MN Neonatal Nurse Practitioner Founder, Lode Star Enterprises

Disclosure Slide • Terry S. Johnson, APN, NNP-BC, CLEC, MN – Financial Arrangements • I currently consult and/or am on the speakers bureaus of • Prolacta Bioscience • Abbott Nutrition Health Institute • I receive financial reimbursement for these services – Images & photographs used in the presentation • From publicly accessed sources – I will make no recommendation for an “off-label” use of any drug or medical device – I hate this disease

NEC: Epidemiology • Incidence – Wide range of variation between centers • • 4 to 11% of all VLBW infants Most common neonatal gastrointestinal emergency Leading cause of morbidity and mortality in this population 1 -3 per 1000 live births – Inverse relationship between incidence & EGA • ~90% of all cases are in premature infants • Term infants - associated with CHD, IUSE (cocaine), peripartum asphyxia, IUGR, hyperviscosity syndrome, NAS Maleshwari A Immunologic and hematoological abnormalities in necrotizing enterocolitis. Clin Perinatol 42 (2015) 567 -585 http: //dx. doi. org/10. 1016/j. clp. 2015. 04. 014 Neu J in (2014) Necrotizing enterocolitis. In Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp, 253 -263 (DOI: 10. 1159/000358474

NEC: Epidemiology • Gender, Race, Seasonality – Males & females equally affected – Black infants > than whites – Role of genetic background may ↑ susceptibility • Cytokine polymorphism - VEGF – No relationship with SES – No seasonal pattern demonstrated – Some “clustering” of patients & cases Srinivasan P et al (2008) Clinics in Perinatology 35(1): 251 -272

NEC: What Is The Emerging Evidence? • Role of Prematurity – Consistent factors associated with the development of NEC are associated with prematurity • • • Immaturity of GI motility Limited digestive ability Impaired circulatory regulation Limited barrier function Abnormal colonization by pathogenic bacteria Underdeveloped intestinal defense mechanisms Srinivasan P et al (2008) Clinics in Perinatology 35(1): 251 -272. 5

NEC: What Is The Emerging Evidence? • Kosloske’s Hypothesis: NEC more likely from • “Quantitative extremes” and/or develops if a • “Threshold of injury” is exceeded “NEC is NOT one disease” Neu J in (2014) Necrotizing enterocolitis. In Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants: Scientific Basis and Practical Guidelines. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp, 253 -263 (DOI: 10. 1159/000358474

NEC: What Is The Emerging Evidence? • GI Symptoms – Feeding intolerance – Delayed gastric emptying and residuals – Vomiting & abdominal distention – Changes in stool pattern – Occult/gross blood in stools – Abdominal tenderness, mass – Erythema/cellulitis of abdominal wall • Systemic Symptoms – Lethargy and/or irritability – Apnea and/or respiratory distress – Temperature instability – Metabolic acidosis – Glucose instability – Poor perfusion/shock – Disseminated Intravascular Coagulation – Oliguria/anuria

NEC: What Is The Emerging Evidence? • Insidious Onset – Evolution of disease over 12 days – Progressive feeding intolerance – Intermittent abdominal distention – Change in stool pattern, consistency – Occult blood in stools – Variable findings • Sudden Onset – Acute catastrophic clinical deterioration – Respiratory decompensation with mixed acidosis – Marked abdominal distention – Gross blood & tissue containing stools – Sepsis – Bacteremia

NEC: What is the Emerging Evidence? • Radiographic Changes – – – Ileus pattern Persistent dilated loop Thickening of bowel wall Pneumatosis intestinalis Pneumoperitoneum Portal venous air • Staging of Radiographs – Stage I: abn distention, ileus – Stage II: pneumatosis, PVG – Stage III: pneumoperitoneum J Ped Surg 37: 1688, 2002 Pediatrics 105: 510, 2000

NEC: What is the Emerging Evidence? • NEC Histologic Involvement – – Mucosal edema Hemorrhage Coagulation necrosis Mucosal ulceration • NEC Intestinal Involvement Terminal ileum – Proximal colon – • Surgical Indication – Pneumoperitoneum – Positive paracentesis – Clinical deterioration • ? Surgical Intervention Persistent dilated loop – Fixed, tender abdominal mass – Portal venous gas –

NEC: What Is The Emerging Evidence? Bell’s Staging of NEC Clinical Findings Bell Is Brok en IA Suspected NEC Temperature instability, apnea, bradycardia ↑ Residuals, mild abdominal distention, occult blood in stools X-ray is normal or a mild ileus present IB Suspected NEC Same as IA but gross blood in stool IIA Definite NEC Mildly ill with same systemic signs Absent bowel sounds, abdominal tenderness X-ray demonstrates ileus, pneumatosis IIB Definite NEC Moderately ill with same systemic signs Mild metabolic acidosis, mild thrombocytopenia Definite abdominal tenderness, abdominal cellulitis, RLQ mass X-ray demonstrates portal vein gas with or without ascites IIIA Advanced NEC Severely ill, bowel intact Hypotension, bradycardia, respiratory & metabolic acidosis, DIC, neutropenia Generalized peritonitis, marked tenderness X-ray demonstrates definite ascites IIIB Advanced NEC Severely ill, bowel perforated X-ray demonstrates pneumoperitoneum

NEC: What is the Emerging Evidence? • Treatment: – Paracentesis in NEC • “Positive” Tap; ~0. 5 cc of free flowing yellow-brown fluid • 40% false negatives – tap negative; bowel dead – Laparotomy or Drain (Blakely, et al: Annals of Surgery 241: 984, 2005) • No difference in survival of NEC patients • Suggestion of improved long term ND with laparotomy – Laparotomy or Drain (Moss, et al: NEJM 354: 2225, 2006) • • No difference in survival at 90 days No difference in dependency on TPN at 90 days No difference in length of hospitalization Type of operation performed for perforated NEC does not influence survival or other clinical outcomes

NEC: What is the Emerging Evidence? • NEC Surgery – 20 -40% of all infants with NEC require surgery – Fatality rates for infants requiring surgery ~50% – 1 in 7 of all NEC hospitalizations end in death – Recurrent NEC has an incidence of 4% to 6% – This rate has not significantly changed over the past 30 years Christensen RD et al Transfusion 2012; 50(5): 1106 -111213 Dominquez KM & Moss L Clin Perinatol 39 (2012) 387– 401 Mohamed A et al Pediatrics 2012; 129(3): 529 -540

NEC: What Is The Emerging Evidence? • Morbidities from SNEC-Associated SBS – – – – – Long term TPN therapy Risk for CLABSI Cholestasis and hepatic failure Small bowel bacterial overgrowth Profound growth disturbances Intestinal failure Bowel transplantation Global developmental delays Profound short and long term economic burden Srinivasan P et al (2008) Clinics in Perinatology 35(1): 251 -272. 14

NEC: What Is The Emerging Evidence? • Short Bowel Syndrome – Most serious long-term complication of NEC – SBS usually is the consequence of extensive intestinal resection, although there are reports of congenital short bowel – NEC is the leading cause of SBS in children accounting for over half of all pediatric cases – SBS occurs in up to one quarter of all infants who develop NEC Navarro, F & Gleason, WA, et al. Neo. Reviews (2009): 10(7); e 333.

NEC: What Is The Emerging Evidence? • Neuro-Developmental – Survivors of NEC have a worse neuro-developmental outcome compared with age-matched controls – In a report of 20 VLBW infants surviving NEC the incidence of severe neuro-developmental retardation was 55% compared with 22% of age matched controls • • • Primarily related to the prematurity Suboptimal head growth Meningitis associated with NEC Prolonged & re-hospitalization Motor delays – trunk control Oral aversion and feeding issues Sato TT, Oldham KT. Abdominal drain placement versus laparotomy for necrotizing enterocolitis with perforation. Clin Perinatol. 2004 Sep; 31(3): 577 -89.

NEC: What Is The Emerging Evidence? • NEC Survivorship Issues – Infants more likely to have long-term complications • Feeding intolerance and chronic GI issues • Growth delays • Neurodevelopmental delay – NEC is an independent risk factor • Abnormal neurologic examination • Severe psychomotor disability of 55% • Higher risk of cerebral palsy, cognitive delays, severe visual impairments Dominquez KM & Moss L Clin Perinatol 39 (2012) 387– 401 Martin CR, Dammann 0, Allred EN J Pediatr 2010: 157(5): 751 -756. e 1 Navarro, F & Gleason, WA, et al. Neo. Reviews (2009): 10(7); e 333 Schulzke SM, Deshpande GC, Patole SK Arch Pediatr Adoles Med (2007); 161(6): 583 -90 Hintz SR et al Pediatrics (2005): 115(3): 696 -703 Vohr BR et al Pediatrics (2000) 105(6): 1216 -26

NEC: What Is The Emerging Evidence? • Cost of NEC in 2011 – Adjusted incremental cost of medical and surgical NEC over and above the average cost incurred for extremely premature infants without NEC Medical NEC $74, 004* per infant (95% confidence interval, $47, 051 -$100, 957) Surgical NEC $198, 040* per infant (95% confidence interval, $159, 261 -$236, 819) * In 2011 US Dollars Srinivasan P et al (2008) Clinics in Perinatology 35(1): 251 -272. 18

NEC: What Is The Emerging Evidence? • What We Knew Then: – – – – 1823 Billard describes first case of NEC 1850 Publication of a series of 25 term/preterm First half of 20 th century reports from Europe 1964 Mizrahi & colleagues used term NEC 1970’s first surgical approach to the disease described 1978 Bell and colleagues classified NEC into 3 stages 2013 - “Despite incremental advances in our understanding of the clinical presentation and pathophysiology of NEC, universal prevention of this serious and often fatal disease continues to elude us even in the twenty-first century. ” Sharma R & Hudak ML Clin Perinatol 40; (2013). 27 -51 doi. org/10. 1016/j. clp. 2012. 012

NEC: What Is The Emerging Evidence? • Prematurity and NEC Distribution of NEC based upon PMA at Birth Single center/202 infants/1991 -2003 Born at 23 to 42 weeks NEC most common at 31 weeks PMA Multicenter/42 infants/2008 -2012 Born at 23 to 32 weeks NEC most common 29 weeks PMA Sharma R & Hudak ML Clin Perinatol 40; (2013). 27 -51 doi. org/10. 1016/j. clp. 2012. 012

NEC: What is the Emerging Evidence? • Common Features in Term Infants with NEC FEATURE EXAMPLE 1. Admitted to an NICU for some reason other Suspected sepsis, congenital heart than NEC (NEC develops as a complication disease, polycythemia during the NICU treatment course) 2. The underlying medical problem involves compromised gastrointestinal perfusion or function Reduced mesenteric perfusion (polycythemia, univenticular heart, sepsis); withdrawal from maternal opioid narcotics. 3. Feeding plans Gavage feeding. Cow’s milk-based formula. Fed a larger volume than breast fed neonates would likely receive. Christensen, RD. et al. 2014. Necrotizing Enterocolitis in Term Infants. Clinics in Perinatology , Volume 40 , Issue 1 , 69 – 78 DOI: http: //dx. doi. org/10. 1016/j. clp. 2012. 007

NEC: What is the Emerging Evidence? • Common Features in Term Infants with NAS/NEC BW (g) Gest Age (w. d. ) Sex Maternal Medications and/or Illicit Drugs Medications Given to the Neonate Before NEC Age When NEC Developed (d) Feedings Before the NEC Diagnosis 2740 38. 6 M Suboxone, Tobacco Amp, Gent 2 Enf 20 (NG+PO) 3232 39. 2 F Nubain, Lortab, Zoloft, Prozac, Tobacco None 2 Breast 3405 39. 5 M Methadone, Tobacco Amp, Gent, Morph, Clonidine 8 Enf 20 (NG+PO) 3015 38. 2 F Methadone, Cocaine Pheno, Morph 19 Sim 20 (NG+PO) Christensen, RD. et al. 2014. Necrotizing Enterocolitis in Term Infants. Clinics in Perinatology , Volume 40 , Issue 1 , 69 – 78 DOI: http: //dx. doi. org/10. 1016/j. clp. 2012. 007

NEC: What is the Emerging Evidence? • Common Features in Term Infants with NAS/NEC BW (g) Gest Age (w. d. ) Sex Maternal Medications and/or Illicit Drugs Medications Given to the Neonate Before NEC Age When NEC Developed (d) Feedings Before the NEC Diagnosis 3470 39. 6 M Methadone Pheno, Morph 9 Sim 20 (NG+PO) 2730 36. 6 M Methadone, Xanax, Tobacco Pheno, Morph 20 Enf 20 2965 38. 1 M Suboxone Clonidine, Pheno 5 Enf 20 2685 39. 4 M Methadone Pheno 5 Enf 20 (NG+PO) 3530 40. 2 F Suboxone, Methadone, Cocaine, Heroin, Ecstasy, Tobacco Clonidine, Morph 8 Sim 20 Christensen, RD. et al. 2014. Necrotizing Enterocolitis in Term Infants. Clinics in Perinatology , Volume 40 , Issue 1 , 69 – 78 DOI: http: //dx. doi. org/10. 1016/j. clp. 2012. 007

NEC: What is the Emerging Evidence?

NEC: What Is The Emerging Evidence? • NEC Presentations – – “Classic NEC” Isolated intestinal perforation Transfusion-Associated NEC (TANEC) NEC in term infants • All increase the risk for – – – Surgical intervention Growth disturbances Neonatal morbidity Developmental delay Death Christensen RD et al Transfusion 2012; 50(5): 1106 -111225 Christensen RD et al Clin Perinatol 2013; 40(1): 69 -78 Dominquez KM & Moss L Clin Perinatol 39 (2012) 387– 401 Mohamed A et al Pediatrics 2012; 129(3): 529 -540

NEC: What Is The Emerging Evidence? • Cost of NEC in May 2015 – Utilizing the California Birth File Dataset, 1375 infants with surgical NEC between 1999 and 2007 were retrospectively propensity score matched according to intervention type. – Total in-hospital costs were converted from longitudinal patient charges. A multivariate mixed effects model compared adjusted costs and mortality between groups. – A multivariate mixed effects model compared adjusted costs and mortality between the groups. Stey A, Barnert ES, et al 2015. Outcomes and Costs of Surgical Treatments of Necrotizing Enterocolitis. Peduatrics, Volume 135, number 5, May 2015

NEC: What Is The Emerging Evidence? • Average Adjusted Cost of NEC – Average adjusted cost for peritoneal drainage followed by laparotomy was $398 173 (95% confidence interval [CI]: 287 784– 550 907), which was more than for peritoneal drainage ($276 076 [95% CI: 196 238– 388 394]; P =. 004) and similar to laparotomy ($341 911 [95% CI: 251 304– 465 186]; P =. 08). • Adjusted mortality from NEC – Was highest after peritoneal drainage (56% [95% CI: 34– 75]) versus peritoneal drainage followed by laparotomy (35% [95% CI: 19– 56]; P =. 01) and laparotomy (29% [95% CI: 19– 56]; P , . 001). – Mortality for peritoneal drainage was similar to laparotomy. • CONCLUSIONS: Propensity score–matched analysis of surgical NEC treatment Stey A, Barnert ES, et al 2015. Outcomes and Costs of Surgical Treatments of Necrotizing Enterocolitis. Peduatrics, Volume 135, number 5, May 2015

NEC: What Is The Emerging Evidence? • Cost of NEC in May 2015 – Propensity score matching performed on 699 infants: TREATMENT ADJUSTED COST STATISTICAL ANALYSIS Peritoneal Drainage n = 101 $276 076 [95% CI: 196 238– 388 394]; P =. 004) Peritoneal Drainage/Laparotomy n = 172 $398 173 (95% confidence interval [CI]: 287 784– 550 907) Laparotomy alone n = 426 $341 911 [95% CI: 251 304– 465 186]; P =. 08) * Average adjusted cost for peritoneal drainage was similar to laparotomy. Stey A, Barnert ES, et al 2015. Outcomes and Costs of Surgical Treatments of Necrotizing Enterocolitis. Peduatrics, Volume 135, number 5, May 2015

NEC: What Is The Emerging Evidence? • Cost of NEC in May 2015 – Propensity score matching performed on 699 infants: TREATMENT ADJUSTED MORTALITY STATISTICAL ANALYSIS Peritoneal Drainage Highest after peritoneal drainage (56% [95% CI: 34– 75]) Peritoneal Drainage/ Laparotomy Second highest (35% [95% CI: 19– 56]; P =. 01) Laparotomy alone (29% [95% CI: 19– 56]; P , . 001) Lowest mortality * Adjusted mortality for peritoneal drainage was similar to laparotomy. Stey A, Barnert ES, et al 2015. Outcomes and Costs of Surgical Treatments of Necrotizing Enterocolitis. Peduatrics, Volume 135, number 5, May 2015

NEC: What Is The Emerging Evidence? “Why is it that simple measures that significantly reduce the incidence and severity of this disease continue to be ignored? Exclusive use of human milk Use of standardized feeding protocols Normalization of the microbiome Jain L Clin Perinatol 40 (2013) xiii-xv Athalye-Jape G More K, Patole S J Matern Fetal Neonatal Med (2012); 1 -8 Swanson J J Perinatol (2013); 33: 1 -2. Underwood MS Pediatr Clin North Am (2013); 60: 189 -207.

NEC: What Is The Emerging Evidence? “ Lack of breast milk may be the commonest immunodeficiency of infancy. ” "Adjunctive Immunologic Interventions in Neonatal Sepsis“ Listed with major clinical strategies , immunologic & pharmacologic therapies Tarnow-Mordi W et al Adjunctive immunologic interventions in neonatal sepsis. In Clinics in Perinatology 37(2) (2010) Hanson LA. Session 1: Feeding and infant development breastfeeding and immune function. Proc Nutr Soc 2007; 66(3): 384 -96.

NEC: What Is The Emerging Evidence? Human Milk Contains Over 100, 000 Components Anti-Microbial Factors Cytokines & Anti-Inflammatory Transporters Secretory Ig. A, Ig. M, Ig. G Lactoferrin Lysozyme Complement C 3 Bifidus factor Antiviral mucins, GAGs Oligosaccharides Tumor Necrosis Factor Interleukins Interferon Prostaglandins Platlete –Activating Factor A-1 anti-trypsin A-1 anti-chymotrypsin Lactoferrin Folate binder Cobalamin binder Ig. F binder Thyroxine binder Corticosteroid binder Hormones Digestive Enzymes Growth Factors Others Insulin Prolactin Thyroid hormones Corticosteroids Oxytocin Calcitonin Parathyroid hormone Erythroppoietin Amylase Bile acid stimulating esteras Bile acid-stimulating lipase Lipoprotein lipase Ribonuclease Epidermal (EGF) Nerve (NGF) Insulin-like (IGF) Transforming (TGF) Polyamines Lycopene Lutein Leptin DNA & RNA Casomprphins ¶-sleep peptides Stem cells

NEC: What Is The Emerging Evidence? • AAP Policy on Breastfeeding & Use of Human Milk 2012 • Human milk is species specific • All substitute feeding preparations differ markedly from it, making human milk uniquely superior for infant feeding • Its the reference or normative model against which all alternative feeding methods must be measured • Supports the use of banked human milk as the “first alternative” to own mother’s milk AAP SECTION ON BREASTFEEDING http: //pediatrics. aappublications. org/content/early/2012/02/22/peds. 2011 -3552. full. pdf+html Pediatrics; originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? • “Milk as Medicine” – A substance or preparation of treating disease, something that effects well-being – The science and art of dealing with the maintenance of health and the prevention, alleviation or cure of disease – Professionals referencing human milk as a “medicine” that “only a mother can provide” Kim JH & Froh EB (2012) JOGNN, 41, 114 -121; 2012. DOI: 10. 1111/j. 1552 -6909. 2011. 01313. x Rodriquez NA, Meier PP, Groer, MW , Zeller JM, Engstrom JL & Fogg L (2010). Advances in Neonatal Care, 10(4) pp. 206 -212.

NEC: What Is The Emerging Evidence? • “Milk as Medicine” – “Human milk is an evolutionary wonder whereby the lactating mother produces a species-specific nutritional and biologically active product that confers the best health to the human offspring”. – “Major components of human milk are not primarily for nutrition, but for host defense” Hanson, LA Immunobiology of human milk (2004). Kim JH & Froh EB (2012) JOGNN, 41, 114 -121; 2012. DOI: 10. 1111/j. 1552 -6909. 2011. 01313. x

NEC: What Is The Emerging Evidence? • Immunonutrition “The modulation of the immune and inflammatory responses in critically ill patients with the use of enteral feedings enriched with immune-enhancing ingredients”. Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002. “The potent benefits of human milk are such that all preterm infants should receive human milk. ” American Academy of Pediatrics Breastfeeding and the use of human milk Section on Breastfeeding Pediatrics originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? • AAP Policy on Breastfeeding & Use of Human Milk 2012 – The potent benefits of human milk are such that all preterm infants should receive human milk – Mother’s own milk, fresh or frozen, should be the primary diet – If mother’s own milk is unavailable pasteurized human donor milk should be used American Academy of Pediatrics. Breastfeeding and the Use of Human Milk. Section on Breastfeeding. [originally published online February 27, 2012]. Pediatrics. DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? Dose-Response Benefits of Breastfeeding Condition % Lower Risk Breastfeeding Comments ORc 95% CI Otitis media 23 Any - 0. 77 0. 64 -0. 91 Otitis media 50 ≥ 3 or 6 mo Exclusive BF 0. 50 0. 36 -0. 70 Recurrent OM 77 Exclusive BF ≥ 6 mod Compared with BF to <6 mod 1. 95 1. 06 -3. 59 URTI 63 >6 mo Exclusive BF 0. 30 0. 18 -0. 74 ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BF, breastfeeding; HM, human milk; Respiratory syncytial virus. a Pooled data. b % lower risk refers to lower risk while BF compared with feeding commercial infant formula or referent group specified. c OR expressed as increase risk for commercial formula feeding. d Referent group is exclusive BF ≥ 6 months. American Academy of Pediatrics Breastfeeding and the use of human milk Section on Breastfeeding Pediatrics originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? Dose-Response Benefits of Breastfeeding Condition % Lower Risk Breastfeeding Comments ORc 95% CI LRTI 72 ≥ 4 mo Exclusive BF 0. 28 0. 14 -0. 54 LRTI 77 Exclusive BF ≥ 6 mo Compared with BF 4 - <6 mo 4. 27 1. 27 -14. 35 Asthma 40 ≥ 3 mo Atopic family history 0. 60 0. 43 -0. 82 Asthma 26 ≥ 3 mo No atopic family history 0. 74 0. 60 -0. 92 ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BF, breastfeeding; HM, human milk; Respiratory syncytial virus. a Pooled data. b % lower risk refers to lower risk while BF compared with feeding commercial infant formula or referent group specified. c OR expressed as increase risk for commercial formula feeding. d Referent group is exclusive BF ≥ 6 months. American Academy of Pediatrics Breastfeeding and the use of human milk Section on Breastfeeding Pediatrics originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? Dose-Response Benefits of Breastfeeding Condition % Lower Risk Breastfeeding Comments ORc 95% CI RSV Bronchiolitis 74 >4 mo - 0. 26 0. 074 -0. 9 NEC 77 NICU stay Preterm infants; exclusive HM 0. 23 0. 51 -0. 94 Atopic dermatitis 27 >3 mo Exclusive BF; (-) family history 0. 84 0. 59 -1. 19 Atopic dermatitis 42 >3 mo Exclusive BF; (+) family history 0. 58 0. 41 -0. 92 ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BF, breastfeeding; HM, human milk; Respiratory syncytial virus. a Pooled data. b % lower risk refers to lower risk while BF compared with feeding commercial infant formula or referent group specified. c OR expressed as increase risk for commercial formula feeding. d Referent group is exclusive BF ≥ 6 months. American Academy of Pediatrics Breastfeeding and the use of human milk Section on Breastfeeding Pediatrics originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? Dose-Response Benefits of Breastfeeding Condition % Lower Risk Breastfeeding Comments ORc 95% CI Gastroenteritis 64 Any - 0. 36 0. 32 -0. 40 Inflammatory Bowel Disease 31 Any - 0. 69 0. 51 -0. 94 Obesity 24 Any 0. 76 0. 67 -0. 86 Celiac Disease 52 > 2 mo 0. 48 0. 41 -0. 89 Gluten exposure when breastfeeding ALL, acute lymphocytic leukemia; AML, acute myelogenous leukemia; BF, breastfeeding; HM, human milk; Respiratory syncytial virus. a Pooled data. b % lower risk refers to lower risk while BF compared with feeding commercial infant formula or referent group specified. c OR expressed as increase risk for commercial formula feeding. d Referent group is exclusive BF ≥ 6 months. American Academy of Pediatrics Breastfeeding and the use of human milk Section on Breastfeeding Pediatrics originally published online February 27, 2012; DOI: 10. 1542/peds. 2011 -3552

NEC: What Is The Emerging Evidence? • “Critical Exposure Periods” – For the use of Human Milk • Colostrum as the transition from amniotic fluid • Transition from colostrum to mature milk feedings • Human milk feedings throughout the NICU stay • Human milk feedings after NICU, after discharge Labbok M, Krasovec K. Toward consistency in breastfeeding definitions. Stud Fam Plann 1990; 21(4); 226 -30. Meier PP, Engstrom JL, Patel AL, Jegier BJ & Bruns, NE. Improving the Use of Human Milk During and After the NICU Stay. Clin Perinatol 37 (2010) 217– 245 doi: 10. 1016/j. clp. 2010. 013.

NEC: What Is The Emerging Evidence? • “Critical Dosage” – For the use of Human Milk • Definitions of “Breastfeeding” • Definitions of “human milk fed” • Calculating the percentage of human milk feedings • “Exclusive human milk diet” • Quality improvement strategies • Lactation support, lacto-engineering • Maintenance of maternal milk volume Labbok M, Krasovec K. Toward consistency in breastfeeding definitions. Stud Fam Plann 1990; 21(4); 226 -30. Meier PP, Engstrom JL, Patel AL, Jegier BJ & Bruns, NE. Improving the Use of Human Milk During and After the NICU Stay. Clin Perinatol 37 (2010) 217– 245 doi: 10. 1016/j. clp. 2010. 013.

NEC: What Is The Emerging Evidence? • “Causal Relationship” – For the use of Human Milk • Dose response relationship • Increased percentage/volume of human milk intake – Decrease in risk of NEC LOS/NEC p < 0. 01 – Decrease in risk of death Schanler, PEDIATRICS 1999; 103: 1150 – Decrease in risk of LOS sepsis – Decrease in days of TPN Lucas, A. ; Cole, T. J. Lancet 1990 (ii) 1519 -1522 Schanler, Pediatrics 1999; 103: 1150 Sullivan S, Schanler RJ, Kim JH et al. J Pediatr 2010 DOI: 10. 1016/j. jpeds. 2009. 10. 04044 Ramani M & Ambalavanan N Clinics in Perinatol 40(1): 1 -10. Patel AL, Johnson TJ, Engstrom JL, et al Journal of Perinatology (2013), 1 -6, 31 January 2013; doi: 10. 1038/jp. 2013. 2 Cristofalo EA, Schanler RJ, Blanco CL et al J Pediatr doi. org/10. 1016/. jpeds. 2013. 07. 011

NEC: What Is The Emerging Evidence? • Benefit of Human Milk Diet to Reduce NEC 926 infants with BW’s below 1850 g (mean 1370 g) and mean gestation 31 weeks 100% Formula + EBM* 100% EBM* NEC Rate 7. 2% No BM used NEC Rate 2. 5% NEC Rate 1. 2% When ANY EBM used 52% decrease in NEC When ONLY EBM used 83% decrease in NEC Lucas, A. ; Cole, T. J. Lancet 1990 (ii) 1519 -1522 Reduction in NEC but without a human milk fortifier to support growth velocity needs

NEC: What Is The Emerging Evidence? The Arc of Human Milk Feeding and NEC Studies Sisk 5 (2007) Mc. Guire 3 (2003) Schanler 4 2 Schanler (2007) (1999) 1 Lucas (1990) • 1 Lucas, A. ; Meinzen-Derr 6 (2009) Sullivan 7 (2009) Cole, T. J. Lancet 1990 (ii) 1519 -1522 J; Hurst, Nancy M. ; Lau, Chantal Clinics in Perinatology 1999 (26) 379 -398 • 3 Mc. Guire W & Anthony MY J Pediatr 2003 Jul; 143(1): 137 -8. • 4 Schanler, RJ Am J Clin Nutr 2007 (85[SUPP]) 625 s • 5 Sisk PM et al Journal of Perinatology (2007) 27, 428– 433; doi: 10. 1038/sj. jp. 7211758; published online 19 April 2007. • 6 Meinzen-Derr J, et al. J Perinatol. 2009 Jan; 29(1): 57 -62. Epub 2008 Aug 21 • 7 Sullivan S, Schanler RJ, Kim JH, et al. J Peds e- published 2009: DOI 10. 1016/jpeds 2009 -10. 040 • 2 Schanler, Richard

NEC: What Is The Emerging Evidence? n=207 Preterm Infants BW ≤ 1250 g ALL Received Their Mother’s Own Milk Donor Milk When OMM is not available in sufficient quantity Human HMF @ 100 m. L/kg/d @ 40 m. L/kg/d H 100 n=69 H 40 n=71 Preterm Formula When OMM is not available in sufficient quantity Bovine HMF @100 m. L/kg/d B 100 n=69 Study Protocol Sullivan, S et al 10. 1016/j. jpeds. 2009. 10. 040

NEC: What Is The Emerging Evidence? Incidence of Surgical NEC or Death 18 Incidence of NEC or Death 25 16 20 14 12 15 10 8 10 6 4 5 2 0 0 HUM 100 Hum 100: Hum 40: HHMF: BOV: HUM 40 HHMF BOV HUM 100 HUM 40 HHMF BOV HMF @ 100 m. L/kg/d HMF @ 40 m. L/kg/d Hum 100 + Hum 40 Bovine-Based Powdered HMF: @100 m. L/kg/d Sullivan S, et al. J Pediatr 2010 DOI: 10. 1016/j. jpeds. 2009. 10. 040

NEC: What Is The Emerging Evidence? #1 Less NEC on Exclusive Human Milk Diet but Cannot Fortify for Growth Exclusive Human Milk Diet + Human Milk Fortifier Decreases NEC and Achieves Expected Growth Lucas 1990 #2 Fortification with Cow Based Human Milk Fortifier Improves Growth and Long Term Outcomes but NEC remains a clinical issue #3 Less NEC with Higher Percentage of Human Milk in Diet but Fortification with Cow Based Proteins Schanler 1995 #4 Meinzen-Derr 2009 Sullivan 2009 Johnson T (2011)

NEC: What is the Emerging Evidence? • Mucosal Immunologic System (MIS) – Provides a complex mechanical barrier and an inherent defense against pathogens that constantly threaten the human body • Epithelial Cells • Mucous Secretions Pulmonary Gastrointestinal Gastrointestina • Epithelial Cells • Mucous Secretions Genitourinary Jakaitis, Brett M. et al. (2014) Human Breast Milk and the Gastrointestinal Innate Immune System. Clinics in Perinatology , Volume 41 , Issue 2 , 423 - 435

NEC: What is the Emerging Evidence? • Mucosal Immunologic System (MIS) – Evidence suggests that these systems do not work independently, but an integrated network of tissue, cells, and signaling molecules • Epithelial Cells • Mucous Secretions Pulmonary Gastrointestinal Gastrointestina • Epithelial Cells • Mucous Secretions Genitourinary Jakaitis, Brett M. et al. (2014) Human Breast Milk and the Gastrointestinal Innate Immune System. Clinics in Perinatology , Volume 41 , Issue 2 , 423 - 435

NEC: What is the Emerging Evidence? • Mucosal Immunologic System (MIS) – The lining of the GI tract provides the largest interface with the external environment and is critical to host defense. • Epithelial Cells • Mucous Secretions Pulmonary Gastrointestinal Gastrointestina • Epithelial Cells • Mucous Secretions Genitourinary Jakaitis, Brett M. et al. (2014) Human Breast Milk and the Gastrointestinal Innate Immune System. Clinics in Perinatology , Volume 41 , Issue 2 , 423 - 435

NEC: What is the Emerging Evidence? • Mucosal Immunologic System (MIS) – At no time in life is this function more important than shortly after birth. • Epithelial Cells • Mucous Secretions Pulmonary Gastrointestinal Gastrointestina • Epithelial Cells • Mucous Secretions Genitourinary Jakaitis, Brett M. et al. (2014) Human Breast Milk and the Gastrointestinal Innate Immune System. Clinics in Perinatology , Volume 41 , Issue 2 , 423 - 435

NEC: What is the Emerging Evidence? • Colonization of the Gut – First Stage – Birth to one week • Composition of infants evolving microbiota is initially defined by the mother • Role of ROM, labor, SVD exposes infant to maternal GI flora → colonization of maternal flora • Mother’s milk (including colostrum) has specific antibodies and oligosaccharides to support growth of commensal bacteria in infant’s gut

NEC: What is the Emerging Evidence? • Colonization of the Gut – Second Stage – 1 -4 weeks of age • Role of infant’s diet is a major factor • Variation in microbiota and organisms seen in breast fed and formula fed infants • Human milk promotes the growth of Lactobacillus and bifidobacterium species • Human milk has a lower buffering capacity and the acidic milieu potentiates growth of nonpathogenic bacteria

NEC: What Is The Emerging Evidence? • Normal Bacterial Colonization • Abnormal Bacterial Colonization – Colonized with fewer, more virulent organisms – Delayed acquisition of commensal bacteria • Bifidobacteria • Lactobacillus • Bacteroides

NEC: What Is The Emerging Evidence? • Mechanisms of Action Patel RM & Denning PW Clin Perinato 40(2013) 11 -25 http: //dx. doi. org/10. 1016/j. clp. 2012. 002

Ontogeny of the Gut • "Evolutionary Discordance" – For millennia woman have delivered & babies have been born • • • At term With labor After rupture of membranes Delivered vaginally And breastfed – But we have managed to change all of that!

NEC: What Is The Emerging Evidence? • Abnormal Bacterial Colonization Source: Clinics in Perinatology 2013; 40: 11 -25 (DOI: 10. 1016/j. clp. 2012. 002 )

NEC: What Is The Emerging Evidence? • Insults Affecting the Premature Gut – – – – Immaturity of end organ system Mode of delivery Luminal starvation Hypoxic-ischemic reperfusion events Infection/inflammation Antibiotic exposure Non-human milk feedings – Altered GI Colonization Neu J & Bernstein, H Update on host defense and immunonutrients Clinics in Perinatology 29(1); 2002.

NEC: What Is The Emerging Evidence? Factors Influencing the Intestinal Microbiome and Predisposing to NEC Dysbiosis Torrazza RM & Neu J Clin Perinatol 40 (2013) 93108 http: //dx. doi. org/10. 1016/j. clp. 2012. 009

NEC: What Is The Emerging Evidence? • Clinical Outcome: Risk of NEC Patel RM & Denning PW Clin Perinato 40(2013) 11 -25 http: //dx. doi. org/10. 1016/j. clp. 2012. 002

NEC: What Is The Emerging Evidence? • Clinical Outcome: Risk of Mortality Patel RM & Denning PW Clin Perinato 40(2013) 11 -25 http: //dx. doi. org/10. 1016/j. clp. 2012. 002

NEC: What Is The Emerging Evidence? • Clinical Outcome: Risk of Sepsis Patel RM & Denning PW Clin Perinato 40(2013) 11 -25 http: //dx. doi. org/10. 1016/j. clp. 2012. 002

NEC: What Is The Emerging Evidence? • Probiotics and NEC

NEC: What Is The Emerging Evidence? • Probiotics and Mortality

NEC: What Is The Emerging Evidence? • Clinical Protocols Provide – A locally agreed standard to which clinicians and the organization can work and against which they can be audited • Use of Clinical Protocols Allows – Health care providers to offer appropriate diagnostic treatment and care services – Provide quality training to clinical staff – Monitor variance reports to purchasers Open Clinical: Computerized Clinical Guidelines. http: //www. openclinical. org/guidelines. html Last modified: Mon, 8 Jul 2013

Guidelines • Evidence-Based “Statements” • Support quality, consistency, standardization • Difficulty in using Clinical Practice Guidelines Protocols Computerized Clinical Guidelines • Encodes evidence-based recommendations • Readily accessible reference • Timely, patient specific • More specific and rigid • Outline management steps for a single clinical condition • Monitors for variance Clinical Protocols

NEC: What Is The Emerging Evidence? • Kamitsuka, MD, Horton, MK & Williams, MA Pediatrics 105(2); Standardized Feeding Regimen • Cohort study, infants with BW between 1250 -2500 g and <35 wks with a retrospective review of incidence of NEC for 3 -year period before (n=447) and after (n= 446) after implementing feeding regimen • Incidence before 4. 8% and after 1. 1% cases of definite NEC and mean time for onset of NEC ↑ from 5. 9 ± 4. 1 days to 19. 4 ± 16. 3 • Risk of NEC reduced 84% after introduction of feeding schedules; the reduction was independent of birth weight, prenatal steroid exposure, breast milk, day of life of first feed, and the number of days to reach full feeds

NEC: What Is The Emerging Evidence? • Impact of standardized feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. SK Patole & N de Klerk Arch Dis Child Fetal Neonatal Ed 2005; 90: F 147 -F 151. doi: 10. 1136/adc. 2004. 059741. • To systematically review the observational studies reporting incidence of NEC in preterm, low birth weight (LBW) neonates “before” and “after” implementation of a standardized feeding regimen • Epidemiological data strongly suggest that NEC has an iatrogenic component related to variations in clinical practices including feeding strategies

NEC: What Is The Emerging Evidence? • Impact of standardized feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. SK Patole & N de Klerk Arch Dis Child Fetal Neonatal Ed 2005; 90: F 147 -F 151. doi: 10. 1136/adc. 2004. 059741. • Review of the Cochrane Central Review Register of Controlled Trials (CENTRAL), Medline, Embase, Cinahl and proceedings of the Pediatric Academic Societies in July and October 2003. • Six eligible studies (1978 -2003) were identified. A significant heterogeneity was noted between the studies indicating the variations in population characteristics over a period of 25 years.

NEC: What Is The Emerging Evidence? • Impact of standardized feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. SK Patole & N de Klerk Arch Dis Child Fetal Neonatal Ed 2005; 90: F 147 -F 151. doi: 10. 1136/adc. 2004. 059741 Characteristics of Studies Included in the Analysis Authors/Year Weight Group NEC Incidence BEFORE SFR NEC Incidence AFTER SFR Brown et al 1978 LBW 14/1745 1/932 Spritzer et al 1988 < 2 kg 51/529 0/604 -3/937 Kamitsuka et al 2000 LBW 23/477 5/467 Patole et al 2000 VLBW 30/250 NEC 1/298 Premji et al 2002 VLBW 2/100 0/100 Kuzma-Oreilly 2003 * VLBW 62/828 94/2041 * Data from three participating centres

NEC: What Is The Emerging Evidence? • Impact of standardized feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. SK Patole & N de Klerk Arch Dis Child Fetal Neonatal Ed 2005; 90: F 147 -F 151. doi: 10. 1136/adc. 2004. 059741 • Result – Introduction of a standardised feeding regimen reduced the incidence of NEC by 87% – Standardised feeding regimens may provide the single most important global tool to prevent/minimise NEC in preterm neonates – The benefits of SFR may be related to the process of developing and implementing the SFR as well as to the constituents of the SFR itself.

Feeding Protocols: Best Practices • Improved outcomes with a standardized feeding protocol for very low birth weight infants. KR Mc. Callie, HC Lee, O Mayer, RS Cohen, SR Hintz and WD Rhine Journal of Perinatology (2011) 31, S 61–S 67. • Results: Data analyzed on 147 VLBW infants VLBW n NEC ELBW BEFORE Protocol 15/83 18% AFTER Protocol 2/64 P value n NEC BEFORE Protocol 11/31 35% 3% AFTER Protocol 2/26 8% P = 0. 005 P value P = 0. 01

Feeding Protocols: Best Practices “Rather than concentrating on the actual feeding regimen itself, there is evidence that simply implementing a feeding regimen that standardizes nutritional support in an NICU may be the most important factor in optimizing growth while minimizing the risk of NEC. ” Uhing MR & Utpala SGD Clin Perinatol 36 (2009) 165 -176. Patole SK & de. Klerk N Arch Dis Child Fetal Neonatal Ed 2005; 90(2): F 147 -51

Providing human milk to 20 preterm infants will prevent one case of NEC Normlalize the Microbiome The number needed to treat with prophylactic probiotics to prevent 1 case of NEC is 25* *AAP (2010) suggests more research needed to determine the appropriate probiotic species and dosing in this population with an emphasis on the ELBW infants 1 Kamitsuka, MD, Horton, MK & Williams, MA Pediatrics 105(2); February 2000; 379 -384. 2007 http: //www. cincinnatichildrens. org/svc/alpha/h/health-policy/ev-based/nec_vlbw. htm 3 Deshpande G, et al Pediatrics published online Apr 19, 2010. DOI: 10, 1542/peds. 2009 -1301 4 Sullivan S, Schanler RJ, Kim JH, et al. J Peds e- published 2009: DOI 10. 1016/jpeds 2009 -10. 040 2 Exclusive Human Milk Diet Risk of NEC reduced 84% after introduction of standardized feeding regiment Human Milk Feeding 2 Probiotics Use of Feeding Protocol 1 Human Milk Feeding Regiment NEC: What Is The Emerging Evidence? Exclusive Human Milk Diet Providing an exclusive human milk diet including a human milk-based fortifier NEC was reduced 77%3

Presenter Terry S. Johnson, APN, NNP-BC, CLEC, MN Neonatal Nurse Practitioner Founder, Lode Star Enterprises, Inc. 7709 Knottingham Lane Downers Grove, IL 60516 Phone: 630. 881. 2606 Email: lodestar@mindspring. com