How to prevent gut disease in neonates Phillip Gordon Tulane

Topics we will cover NEC (overview) Term NEC Preterm NEC NEC associated with transfusions NEC associated with cows milk intolerance Catastrophic NEC Spontaneous Intestinal Perforations

NEC is increasing The data suggests that nationally, current trends in prematurity and neonatal care have resulted in increased NEC incidence in lower level units. This situation calls for more proactive regional NICUs who can provide support and education to surrounding units.

What is NEC?

It’s not just inflammation, it’s hemorrhagic necrosis Normal NEC The reason that this distinction is important is that the neonatal bowel is utilizing the innate immune system to modulate inflammation rather than adaptive immunity (which kicks in weeks to months later as we introduce food)

It is the innate immune system in combination with external factors that creates a permissive situation for NEC Hemorrhagic necrosis is a common end point that allows us to give an umbrella diagnosis of NEC, but infants with widely variable presentation and severity of disease all have the same pathology – i.e. it’s not a very useful differentiator There are variable combinations of factors and triggers that each distinctly increase the risk of progression to NEC Large cohort analyses have allowed recognition of distinct NEC subgroups, based on their etiologic risk factors, and have been key to new strategies for NEC prevention

Review of term NEC risk factors Hypoxia / Ischemia An immature and naive gut Term NEC Feeding a colonized gut The Classic NEC Triad

NEC risk factors with prematurity Hypoxia / Ischemia An immature and naive gut Term NEC Feeding a colonized gut Preterm NEC Bacterial Overgrowth

The Key differences are: The principle mechanistic difference between term and preterm NEC is that one is triggered by hypoxic-ischemic pre-events, the other by bacterial overgrowth that the bowel cannot contain or tolerate. However, the circumstances in which NEC evolves is quite different in the two populations and thus understanding the co-morbidities and evolution of NEC in each distinct disease process can help us understand the rationale behind prevention strategies.

How do clinical databases see “NEC”? These are the Diagnostic Categories currently available in the Pediatrix Database: Rule out NEC Suspected NEC Medical NEC Surgical NEC Which of these are truly NEC? Clinically, NEC is diagnosed in any child with bowel pneumatosis on x-ray

This is the distribution of NEC and SIP by gestational age This is the distribution of NEC and SIP by gestational age. Most NEC is preterm NEC.

Intermittent aspirates Preterm NEC Pathogenesis (1) Feeding Intolerance of Prematurity / Ileus Intermittent aspirates Loopy Formula Irregular stooling < 80 mL/kg/day

Preterm NEC Pathogenesis (2) Pneumatosis / NEC Stacking Aspirates Ileus Pneumatosis (x-ray) Formula Not stooling 80-120 mL/kg/day

Can we cut the incidence of (preterm) NEC in half today? Human Milk 1 A Standardized Feeding Protocol Christensen, Gordon, Besner , 2010 2 Nurse Ratched 3

What is different about term NEC? They are fed at full feeds almost immediately They have intact G.I. motility (more or less) They are able to feed P.O. Parents have more input into the child’s feeding

Perinatal factors associated with term NEC Lambert , et al., 2007 Out of 5877 infants > 36 weeks, 30 had NEC diagnosed by pneumatosis Other = perinatal hypoxia / ischemia, sepsis or respiratory distress The were 4 common NEC preconditions: 1- cong. heart disease (incidence = 1.5%) 2- shock/sepsis (incidence = 50%) 3- hypoxia/ischemia (incidence = 9%) 4- polycythemia (incidence = 13%) These variables were significantly higher in the NEC cohort than controls All infants but one were rapidly advanced with formula (that infant was fed breast milk fortified with human milk fortifier – thus had the potential for bacterial overgrowth)

Outcomes for Ischemic NEC Lambert , et al., 2007 Feature M/MD (sd, rg, %) Age (days) when NEC was diagnosed 15  12; (12; 1–46) Location of patient when NEC developed Home=2, NICU=28 Transferred to children's hospital for surgical management 8 (27%) Surgery for NEC 7 (23%) Bowel perforation and resection 5 (17%) Total bowel necrosis diagnosed 2 (7%) Survival (%) 26/30 (87%) Length of hospital stay (days) – all 30 patientsb (32; 2–244) Length of hospital stay (days) – 26 survivors (37; 7–145)

Preventing term NEC Term NEC has preconditions that place patient’s at risk. Exclusive feeding of human milk may reduce risk, but this population is rarer and more challenging to capture for standardized feeding protocols (especially in non-tertiary NICUs) and thus may not be as amenable to prevention when compared to preterm NEC. A high index of suspicion for a co-morbid, perinatal risk factors should prompt a controlled feeding advance (50 ml/kg/day on day 1 -> 100 ml/kg/day on day 2 -> 150 ml/kg/day on day 3) to facilitate observation during the period of greatest risk

Transfusion Associated NEC is a subset of Preterm NEC Pneumatosis associated with IVIG Gestation age (weeks) NEC not associated with transfusion Transfusion associated NEC Volume 8, Issue 2 Birth weight (grams)

What are the co-travelers with transfusion-associated NEC? Incidence is decreased in infants receiving breast milk Incidence is decreased in infants whose feedings are held during the time of transfusion Incidence is increased in infants with lowest HCTs Incidence is increased in infants on exclusive formula feeds Incidence is increased in infants who have had a previous transfusion There is no relation to the age of the pRBCs at time of transfusion

Cows Milk Allergy versus NEC We have known for some time that infants with cows milk allergy can present with pneumatosis. More recently, we have seen case studies and case series demonstrating premature infants with multiple episodes of pneumatosis that finally resolve with elemental formula and that are highlighted by eosinophilia in the stool and/or blood which also resolve with elemental formula. These infants have a milder form of NEC that is precipitated principally by relatively early onset of milk allergy (usually not before 4 weeks of life). Gordon et al. J. Perinatol, 2008

Infants who have NEC with eosinophilia are less likely to die Eosinophils N Lived N Died < 5 (76.8%) 1821 (78%) 514 (22%) 5 -10 (13.8%) 328 (81%) 77 (19%) >10 (9.4%) 223 (85.2%) 45 (16.8%) Patients extracted from the Pediatrix database of preterm neonates (< 36 weeks with a diagnosis of medical or surgical NEC from 1997-2009 and also had a reported CBC on the day of diagnosis)

Catastrophic NEC

This is the NEC subgroup we know the least about… Catastrophic NEC This is the NEC subgroup we know the least about… NEC (n = 7099) Lived Died < 7 days > 7 days PERINATAL VARIABLES Median 10-90th p value Maternal Age 26 (19-36) (18-36) NS 0.3 Gestational 30 (25-35) (24-32) 0.001 25 (23-31) 0.01 Birth weight 1.32 (0.72-2.5) 0.82 (0.55-1.6) 0.86 (0.6-1.7) 0.74 (0.5-1.4) APGAR 1 min 7 (2-8) 5 (1-8) APGAR 5 min 8 (6-9) (4-9) (5-9) Age at diagnosis 15 (4-40) 18 (7-42) (7-40) 19 (7-47) Patients extracted from the Pediatrix database of preterm neonates (< 36 weeks with a diagnosis of medical or surgical NEC from 1997-2009 for whom discharge data was available)

There is a trend towards lymphocytosis at presentation in catastrophic NEC Lived Died p value Died < 7 days Died > 7 days CBC data (n) 5569 1494 Avg of WBC 11 (4.9-20.7) 11.2 (4.3-25.9) 0.001 10.5 (3.9-25) 12.1 (4.9-27.2) 0.004 Avg of Hgb 12.8 (9.9-16.9) (9.3-15) 11.8 (9-14.9) 12.5 (9.9-15.2) Avg of Hct 37.4 (29-49) 35.6 (27.6-44.4) 35.1 (27.1-44.2) 36.2 (29.2-44.7) Avg of Plat 288 (117-506) 178 (56-409.3) 198 (59-422) 150 (54-375) Avg of Seg 35 (13-61) 31 (8.5-59) 29 (7-56) 36.3 (12-65.5) Avg of Band 8 (1-29) 13 (2.55-33) (3-32) 12 (2-33.45) NS Avg of Lymph 37 (16-59.3) 34.8 (13.5-62.2) 37.8 (14.5-65) (11-57.35)

We don’t yet know what causes catastrophic NEC but, if I had to guess… These would be the etiologies highest on my list of possibilities: Viral-triggered NEC (Rotavirus, Adenovirus, Norwalk virus, etc.). Some may be coincident with transfusion, therefore some may actually be transfusion-associated NEC Some may be a combination: emerging cows milk allergy, viral challenge and/or transfusion associated, in other words, these sub-group designations are not mutually exclusive The only new potentially preventative measure here is the possible viral aspect, because infants who are part of a NEC cluster need to be quarantined to prevent further spread.

Spontaneous Intestinal Perforations SIP presents as a single or a few isolated perforations most commonly in the ileum of distal jejunum in infants < 1000 grams birth weight. The average day of life 0f presentation is 7 days and the clinical finding is pneumoperitoneum in most cases.

Spontaneous Intestinal Perforations SIP is not NEC. The simplest evidence for this is the histology. NEC has mucosal necrosis, SIP doesn’t. SIP has focal muscularis necrosis, NEC doesn’t. Even in cases of SIP that are occult and the perforation has gone undiagnosed for days to weeks, this histopathology remains remarkably consistent (with only minimal total tissue necrosis at the peforation margins. NEC Normal SIP

Risk factors associated with SIP Extreme prematurity / low birth weight (< 100o grams) Early postnatal steroids (dexamethasone or hydrocortisone) Early postnatal indomethacin (in the first 4 days of life) The combination of early steroids and early indomethacin Early postnatal ibuprofen Prenatal indomethacin, given shortly before delivery of an extremely premature infant (for tocolysis) SGA infants who are also premature. High endogenous cortisol levels in the first days of life Candida chorioamnionitis

Summary of surgical outcomes data for SIP & NEC SIP preferentially treated by drain is associated with increased cPVL and likely increased neurodevelopmental insult (NDI) compared to age matched controls Surgical NEC has a higher mortality than SIP and has a greater risk of NDI when compared to SIP cohorts and controls, but all available data suffers from SIP contamination in currently published NEC cohorts. It is probable that NDI associated with NEC and SIP could be improved by choosing primary laparotomy rather than drain. It is imperative that future outcome studies differentiate SIP from NEC in the primary disease cohorts

SIP and NEC are preventable diseases No early steroids or NSAIDs Use feeding guidelines, initiate feeding advances early Promote breast milk feeding at every opportunity Use glycerin as appropriate Minimize blood draws and transfusions (draw retics with HCTs) Wash your hands between babies Pay attention to aspirates that “stack”, ignore those that don’t, ignore all colors but dark green. Don’t over wean the respiratory support or the isolette temp while advancing feeds Quarantine infants with NEC to minimize the chance of NEC clusters (contact precautions).

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