CAN WE PREVENT
NECROTIZING ENTEROCOLITIS (NEC)?
Reese H Clark, MD
Vice-President and Co-Director
The Center for Research, Education, and Quality
Pediatrix Medical Group
OBJECTIVES
• To define the term NEC
• Review the evidence that NEC can be reduced.
• Discuss implementation of specific
approaches to reduce NEC
WHAT IS NEC?
• It is a window of developmental vulnerability in which innate
immunity can be over-activated and the resulting inflammation
triggers necrotic obliteration of the neonatal intestinal mucosa
• It occurs at a stereotypic time in relation to the gestation at birth
(the younger the gestation the later the onset)
• It requires that the infant be fed (substantially)
• It almost never occurs when the intestinal immune system is
mature and intact, even if other risk factors are present
• The triggering of NEC is a multi-factorial phenomena, much like
BPD, many risk factors heighten neonatal intestinal inflammation
until an irreversible “waterline” is surpassed and mucosal necrosis
proceeds.
DIFFERENTIAL DIAGNOSIS OF NEC
•
•
•
•
Spontaneous ileal perforation
Intestinal volvulus
Sepsis with ileus
Term infant: consider invasive enteritis (viral,
salmonella/yersinia/c.diff/E. coli 0157)
• Late onset consider allergic colitis
PROPOSED DEFINITION FOR NEC
PHILL GORDON
• Acute abdominal distention from focal or global ileus while on > 40
ml/kg/day of enteral feeds
– AND
•
•
•
•
Radiographic pneumatosis on day of diagnosis
OR persistent platelet consumption > 4 days from day of diagnosis
OR portal air on the day of diagnosis (not to include iatrogenic)
OR surgical / autopsy confirmation of > 4 cm of necrotic bowel with
pneumatosis that extends beyond the immediate margins of a solitary
perforation. Focal gangrene that principally affects the serosa surrounding
a solitary perforation should not be labelled “NEC”.
• Things that should NOT be used as diagnostic criteria for NEC
– Pneumoperitoneum – confounded by SIP / congenital sources of perforation
– Bloody stools – confounded by cows milk intolerance / colitis / iron
supplements
In about one-third of cases, NEC is suspected but not confirmed (stage I), and symptoms
resolve gradually in these infants.
In 25 to 40 percent of cases, the progression of NEC is fulminant with signs of peritonitis
and sepsis, and the rapid development of DIC and shock (stage III).
Spontaneous Intestinal Perforations
• Is unrelated to feeds
• Is always a surgical disease (and thus is a
common surgical NEC contaminant)
• Occurs at an earlier time of life than NEC
• Affects a younger gestational population
• Has unique risk factors (early postnatal steroids
and NSAIDs) which are not associated with NEC
• Has different histology/pathology from NEC
http://en.wikipedia.org/wiki/File:Neonatal_necrotizing_enterocolitis,_gross_pathology_20G0021_lores.jpg
SIP
SPONTANEOUS INTESTINAL PERFORATION (SIP)
• Typically found at the terminal ileum.
• Occurs primarily in premature, very low birth weight
(VLBW, birth weight <1000 g) infants
• SIP generally presents within the first 10 days of life as an
acute onset of abdominal distension and hypotension. The
classical physical finding is a black-bluish discoloration of
the abdominal wall. In contrast, abdominal wall erythema,
crepitus, and induration commonly seen with NEC are not
usually present in infants with SIP.
• Long-term survival of infants with SIP has improved over
the past 30 years with reported survival rates of 64 to 90
percent. However, survivors are at risk for
neurodevelopmental impairment.
Timing
SYMPTOMS
(MAY COME ON SLOWLY OR SUDDENLY)
•
•
•
•
•
•
•
•
Abdominal distention
Apnea and bradycardia
Blood in the stool
Diarrhea
Feeding intolerance
Lethargy
Temperature instability
Vomiting
PROPOSED DEFINITION FOR NEC
PHIL GORDON
• Acute abdominal distention from focal or global ileus while on > 40
ml/kg/day of enteral feeds
– AND
•
•
•
•
Radiographic pneumatosis on day of diagnosis
OR persistent platelet consumption > 4 days from day of diagnosis
OR portal air on the day of diagnosis (not to include iatrogenic)
OR surgical / autopsy confirmation of > 4 cm of necrotic bowel with
pneumatosis that extends beyond the immediate margins of a solitary
perforation. Focal gangrene that principally affects the serosa surrounding
a solitary perforation should not be labelled “NEC”.
• Things that should NOT be used as diagnostic criteria for NEC
– Pneumoperitoneum – confounded by SIP / congenital sources of perforation
– Bloody stools – confounded by cows milk intolerance / colitis / iron
supplements
Who gets NEC?
NEC By EGA
WHAT KILLS INFANTS WITH NEC
IS NOT CLEAR
RISK FACTORS ASSOCIATED
WITH DEATH FROM NEC
• Lower estimated gestational age
• Lower birth weight
• Treatment with assisted ventilation on the day of diagnosis of
NEC
• Treatment with vasopressors at the time of diagnosis
• Black race
• Patients who received only ampicillin and gentamicin on the
day of diagnosis were less likely to die.
RISK FACTORS ASSOCIATED
WITH RAPID DEATH FROM NEC
• Two-thirds of NEC deaths occurred quickly (<7 days
from diagnosis), with a median time of death of one
day from time of diagnosis.
• Infants who died within 7 days of diagnosis had a
higher birth weight, more often were on
vasopressors and high frequency ventilation at the
time of diagnosis compared with patients who died
at 7 or more days.
70%
Died >= 7 days
60%
Died <7 days
50%
40%
30%
20%
10%
0%
40 (n=99)
39 (n=97)
38 (n=128)
Estimated Gestational Age
37 (n=120)
36 (n=153)
35 (n=260)
34 (n=392)
33 (n=432)
32 (n=502)
31 (n=535)
30 (n=521)
29 (n=592)
28 (n=678)
27 (n=616)
26 (n=639)
25 (n=579)
24 (n=515)
23 (n=225)
Mortality in Neonates with NEC
Clark RH, Gordon P, Walker WM, Laughon M, Smith PB, Spitzer
AR. Characteristics of patients who die of necrotizing
enterocolitis. J Perinatol. 2012;32:199-204.
PREVENTING NEC
Necrotizing enterocolitis: current perspectives
Phani Kiran Yajamanyam, Shree Vishna Rasiah, and Andrew K Ewer
IMPORTANT INTERVENTIONS THAT REDUCE
THE RISK OF NEC
• Human milk (both mother’s & donor milk programs)
• Standardized feeding guidelines (including early
initiation)
• Probiotics
• Antibiotic stewardship
• Optimization of enteral nutrition and growth
• Elimination of H2 blockers and acid pump suppressors
• Elimination of cows milk products
• Transfusion protocols and transfusion outcome
monitoring
HUMAN MILK
Adjusted survival curves for necrotizing enterocolitis (NEC) or death by proportion of human milk to
total intake over the first 14 days of life. Survival curves adjusted for birth weight, small for gestational
age, race, patent ductus arteriosus (PDA), antenatal steroids, duration of mechanical ventilation and Network
Center. The numbers on the graph (0, 0.25, 0.50, 0.75 and 1.0) represent the proportion of total intake that is
human milk. Survival curves represent predicted survival time free of NEC or death and do not directly
correspond to the number of infants.
Meinzen-Derr J, et. al. Role of human milk in extremely low birth weight infants' risk of necrotizing enterocolitis or
death. J Perinatol. 2009 January ; 29(1): 57–62. RR = 0.83 (CI 0.72, 0.96) for each 10% increase in the proportion of
total intake as HM.
Quigley M, McGuire W. Formula milk versus donor breast milk
for feeding preterm or low birth weight infants Updated.
Published Online: 22 April 2014
• Nine trials, in which 1070 infants participated, fulfilled the inclusion
criteria. Four trials compared standard term formula versus donor breast
milk and five compared nutrient-enriched preterm formula versus donor
breast milk.
• Only the two most recent trials used nutrient-fortified donor breast milk.
The trials contain various methodological quality weaknesses, specifically
uncertainty about adequate allocation concealment methods in three
trials and lack of blinding in most of the trials.
• Formula-fed infants had higher in hospital rates of increase in weight
[mean difference (MD): 2.58 (95% confidence interval (CI) 1.98 to 3.71)
g/kg/day], length [MD 1.93 (95% CI 1.23 to 2.62) mm/week] and head
circumference [MD 1.59 (95% CI 0.95 to 2.24) mm/week].
• No effect on post-discharge growth rates or neurodevelopmental
outcomes.
• Formula feeding increased the risk of necrotizing enterocolitis: typical
risk ratio 2.77 (95% CI 1.40 to 5.46); risk difference 4% (95% CI 2% to 7%).
Vohr BR, et al. Persistent beneficial effects of breast milk ingested in the
neonatal intensive care unit on outcomes of extremely low birth weight
infants at 30 months of age. Pediatrics 2007;120(4):e953-e959.
• For every 10 mL/kg per day increase in breast milk
– Mental Developmental Index increased by 0.59
points,
– Psychomotor Developmental Index by 0.56 points,
– Behavior percentile score by 0.99 points
– Risk of rehospitalization between discharge and
30 months decreased by 5%.
MEAN MDI AND PDI SCORES AT 18 AND 30 MONTHS ACCORDING TO ANY BM FEEDING.
Vohr B R et al. Pediatrics 2007;120:e953-e959
©2007 by American Academy of Pediatrics
Superhero sugars in breast milk make the newborn gut safe for beneficial bacteria
by Jessica Shugart 2:05pm, December 27, 2013
https://www.sciencenews.org/article/mother-lode
Superhero sugars in breast milk make the newborn gut safe for beneficial bacteria
by Jessica Shugart 2:05pm, December 27, 2013
https://www.sciencenews.org/article/mother-lode
COLOSTRUM FEEDINGS
• Colostrum is a pre-milk fluid rich in
immunoglobulins and immune cells that is
produced during the first 24-48 hours
postpartum.
• It is very like a medicine and may play an
important role in protecting preterm infants
HUMAN MILK - DONOR
Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, KiechlKohlendorfer U, et al. Randomized trial of exclusive human milk versus
preterm formula diets in extremely premature infants. J Pediatr.
2013;163:1592-1595.
• A multicenter randomized trial in extremely preterm infants
compared a feeding regimen based exclusively on human
milk (donor breast milk with fortifier derived from human
milk) to one using preterm formula and fortifier derived
from cow’s milk
• Infants were eligible if their mothers did not provide their
own breast milk
• Infants fed with the human milk regimen had a shorter
duration of parenteral nutrition and a lower rate of
surgical NEC, but the rate of NEC overall was not
statistically different in the two groups.
• The incidence of NEC in the group fed formula was very
high (21%), much higher than the usual rate of NEC
34
Cristofalo EA, Schanler RJ, Blanco CL, Sullivan S, Trawoeger R, Kiechl-Kohlendorfer U, et
al. Randomized trial of exclusive human milk versus preterm formula diets in
extremely premature infants. J Pediatr. 2013;163:1592-1595.
35
Human Breast Milk- Donor
Meta-analysis showed risk of NEC increased by 2.5 if fed formula vs. DBM
Donor BM likely has protective effect against NEC as well
Quigley, et al. Cochrane 2008
36
Hair AB, Hawthorne KM, Chetta KE, Abrams SA. Human milk
feeding supports adequate growth in infants </= 1250 grams
birth weight. BMC Res Notes. 2013;6:459.
• Single center, prospective observational cohort study,
preterm infants weighing ≤ 1250 g BW were fed an
exclusive human milk-based diet until 34 wks
postmenstrual age
• Evaluated 104 infants with mean EGA of 27.6 ± 2.0 wks and
BW of 913 ± 181 gm
• Human milk fortification with donor human milk derived
fortifier was started at 60 mL/kg/d and advanced to
provide 6 to 8 additional kilocalories per ounce
• Weight gain was 24.8 ± 5.4 g/kg/day with length 0.99 ± 0.23
cm/week and head circumference 0.72 ± 0.14 cm/week.
• Weight velocity was affected by day of fortification and day
of full feeds
Feeding
Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to
prevent necrotizing enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev. 2013 Mar 28;3:CD001241.
• Five randomized controlled trials in which a total of 588 infants
participated.
• Few participants were extremely preterm, extremely low birth weight or
growth restricted.
• The trials defined slow advancement as daily increments of 15 to 20 ml/kg
and faster advancement as 30 to 35 ml/kg.
• Meta-analyses did not detect statistically significant effects on the risk of
necrotizing enterocolitis (typical risk ratio (RR) 0.97, 95% confidence
interval (CI) 0.54 to 1.74) or all-cause mortality (RR 1.41, 95% CI 0.81 to
2.74).
• Infants who had slow advancement took significantly longer to regain birth
weight (reported median differences two to six days) and to establish full
enteral feeding (two to five days).
Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to
prevent necrotizing enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev. 2013 Mar 28;3:CD001241.
Clyman R, et al. Enteral feeding during indomethacin and ibuprofen treatment
of a patent ductus arteriosus. J Pediatr. 2013;163:406-411.
•
•
•
•
•
23(1/7)-30(6/7) weeks' gestation
weighed 401-1250 g at birth,
received maximum enteral volumes </=60 mL/kg/d,
and were about to be treated with indomethacin or ibuprofen.
Randomized at 6.5 +/- 3.9 days to receive "trophic" feeds ("feeding" group,
n = 81: indomethacin 80%, ibuprofen 20%) or no feeds ("fasting/NPO"
group, n = 96: indomethacin 75%, ibuprofen 25%) during the drug
administration period.
• Infants randomized to the "feeding" arm required fewer days to reach the
study's feeding volume end point (120 mL/kg/d).
• Although the enteral feeding end point was reached at an earlier postnatal
age, the age at which central venous lines were removed did not differ
between the 2 groups.
• There were no differences between the 2 groups in the incidence of
infection, necrotizing enterocolitis, spontaneous intestinal perforation, or
other neonatal morbidities.
ACID REDUCING AGENTS DO NOT
WORK AND MAY BE DANGEROUS
Efficacy and Safety of Once-Daily Esomeprazole for the Treatment of
Gastroesophageal Reflux Disease in Neonatal Patients. Journal of Pediatrics
DOI: 10.1016/j.jpeds.2013.05.007
• There were no significant differences between the
esomeprazole and placebo groups in the percentage
change from baseline in the total number of GERDrelated signs and symptoms (-14.7% vs -14.1%,
respectively).
• Mean change from baseline in total number of reflux
episodes was not significantly different between
esomeprazole and placebo (-7.43 vs -0.2,
respectively); however, the percentage of time pH was
<4.0 and the number of acidic reflux episodes >5
minutes in duration was significantly decreased with
esomeprazole vs placebo (-10.7 vs 2.2 and -5.5 vs 1.0,
respectively; P ≤ .0017).
44
Ranitidine is associated with infections,
necrotizing enterocolitis, and fatal outcome in
newborns.
34/91 (37%) vs 18/183 (10%)
OR=5.5 [2.9, 10.4]
9.8 vs 1.6%
OR=6.6 [1.7-25.0]
9.9 vs 1.6%
OR=6.6 [1.7-25.0]
Terrin G, et al. Pediatrics 2012;129(1):e40-e45
Terrin G, et al. Pediatrics 2012;129(1):e40-e45
Gupta RW, Tran L, Norori J, Ferris MJ, Eren AM, Taylor CM, et al. Histamine-2
receptor blockers alter the fecal microbiota in premature infants. J Pediatr
Gastroenterol Nutr 2013 Apr;56(4):397-400
• The objective of the present study was to test the hypothesis that
histamine-2 receptor (H2-) blockers alter colonic bacterial
colonization by analyzing and comparing the fecal microbiota in
premature infants with and without H2-blocker therapy using
sensitive molecular biological techniques.
• Seventy-six premature infants </=1500 g or <34 weeks gestation
were enrolled in this case-controlled, cross-sectional study. Stool
samples were collected from 25 infants receiving H2-blockers and
51 babies who had never received them.
• Proteobacteria and Firmicutes were the major phyla contributing to
fecal microbial communities.
• Microbial diversity was lower, relative abundance of Proteobacteria
(primarily of the family Enterobacteriaceae) was increased, whereas
that of Firmicutes was decreased in the stools of infants receiving
H2-blockers compared with those who had never received them.
Antibiotic Stewardship
Prolonged Antibiotic Therapy for "Culture-Negative" Sepsis in
Preterm Infants: It's Time to Stop!
• Prolonged antibiotic therapy is more related to
institutional decisions than severity of illness
• Biological plausibility to explain some of these
negative associations.
– Antibiotic therapy affects gastrointestinal flora of preterm
infants which can impact the development of NEC and
late-onset sepsis, both of which can lead to death.
– Elimination of commensal flora allows for colonization by
multi-drug resistant organisms and fungi
Cantey JB. J Pediatr. 2011;159:707-708.
Association Of Initial Empirical Antibiotic Treatment With Necrotizing
Enterocolitis And Death For Extremely Low Birth Weight Infants
• Retrospective cohort analysis of ELBW infants admitted 1998-2001.
• Defined initial empirical antibiotic treatment duration as continuous days
of antibiotic therapy started in the first 3 postnatal days with sterile
culture results.
• Prolonged empirical antibiotic therapy (≥5 days)
• 4039 infants survived >5 days and included in study
• Median therapy duration was 5 days (range: 1-36 days);
• 2147 infants (53%) received prolonged empirical therapy (center range:
27%-85%).
• Multivariable analyses (adjusted for GA, Apgar score, race,
center) prolonged therapy was associated with increased
odds of necrotizing enterocolitis or death and death alone.
Cotten, Pediatrics, 2009.
Antimicrobial Exposure and NEC
Yale cohort replicates association reported by Cotten
Alexander. J Pediatr. 2011;159(3):392-7.
Probiotics
Probiotic effects on late-onset sepsis in very preterm infants:
a randomized controlled trial.
Pediatrics. 2013 Dec;132(6):1055-62
•
•
•
•
•
•
•
A prospective multicenter, double-blinded, placebo-controlled, randomized trial
compared daily administration of a probiotic combination (Bifidobacterium
infantis, Streptococcus thermophilus, and Bifidobacterium lactis, containing 1 ×
10(9) total organisms) with placebo (maltodextrin) in infants born before 32
completed weeks' gestation weighing <1500 g.
The primary outcome was at least 1 episode of definite late-onset sepsis.
October 2007 and November 2011
1099 very preterm infants from Australia and New Zealand were randomized.
Rates of definite late-onset sepsis (16.2%), NEC of Bell stage 2 or more (4.4%), and
mortality (5.1%) were low in controls, with high breast milk feeding rates (96.9%).
No significant difference in definite late-onset sepsis or all-cause mortality was
found
Probiotic combination reduced NEC of Bell stage 2 or more (2.0% versus 4.4%;
relative risk 0.46, 95% confidence interval 0.23 to 0.93, P = .03; number needed to
treat 43, 95% confidence interval 23 to 333).
William Tarnow-Mordi and Roger Soll. Probiotic Supplementation in Preterm Infants:
It Is Time to Change Practice.
The Journal of Pediatrics Volume 164, Issue 5 , Pages 959-960, May 2014.
• Probiotic supplementation in preterm infants is perhaps the best
studied yet least used therapy in neonatal medicine.
• All recently published meta-analyses have reported significant
impacts on important clinical outcomes.
• In the updated Cochrane meta-analysis, which includes 24 trials,
there is a significant decrease in necrotizing enterocolitis (NEC)
(relative risk 0.43, 95% CI 0.33-0.56; risk difference of 3%; and allcause mortality (RR 0.65, 95% CI 0.52-0.81).
• Length of stay was 3-4 days shorter.
• There was no probiotic-related sepsis, although this is rarely
reported outside trials.
• Probiotics are still infrequently used in North America. In 2012, only
8%-9% of very low birth weight (VLBW) infants in the Vermont
Oxford Network received probiotics.
FEASIBILITY
• How do we know that we can actually impact
NEC on a national level?
• Because we already have…
100,000 babies Campaign…
(credit to Dan Ellsbury & Robert Ursprung)
• Enhance Nutrition:
– Maximize breast milk use, use a standardized feeding protocol,
and provide early protein
• Improve Medication Use:
– Optimize use of antenatal steroids, caffeine, and surfactant.
Optimize antibiotic choice and exposure, decrease
cephalosporin use, H-2 blocker use, and postnatal steroid use,
standardize oxygen management
• Optimize Central Line Use:
– Standardized central line insertion process, standardized central
line maintenance process, and minimize central line duration
• Reduce Suboptimal Admission Temperatures:
– Standardize initial thermal management
GI Medications Use Rates
(Per 1000 Patients Based Counted Only Once Per Patient)
Source: Pediatrix Clinical Data Warehouse
Since 100,000 babies…
500-1500g inborn only, high volume units only
Change in Reports of Medical or Surgical NEC in PDX or
VON (Inborn, 401-1500 grams = VLBW All)
Site Variability in NEC Observed Rate
5 year period, Inborn, VLBW
More than 0 Extra Cases Less than 0 fewer Cases
5 year period, Inborn, VLBW
Case Avoided
Vaidyanathan Ganapathy et al. Long term healthcare costs of infants who
survived neonatal necrotizing enterocolitis: a retrospective longitudinal study
among infants enrolled in Texas Medicaid. BMC Pediatrics 2013, 13:127
• Two hundred fifty NEC survivors (73 with surgical NEC) and 2,909
matched controls were available for follow-up.
• Medical NEC infants incurred significantly higher healthcare costs
than matched controls between 6–12 months of age (mean
incremental cost = US$ 5,112 per infant).
• No significant difference in healthcare costs between medical NEC
infants and matched controls was seen after 12 months.
• Surgical NEC survivors incurred healthcare costs that were
consistently higher than that of matched controls through 36
months of age.
• The mean incremental healthcare costs of surgical NEC infants
compared to matched controls between 6–12, 12–24 and 24–36
months of age were US$ 18,274, 14,067 (p < 0.01) and 8,501 (p =
0.06) per infant per six month period, respectively.