Transcript Necrotizing Enterocolitis: What Do We Know Now?

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
1-2 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
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 rare
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.
NeoReviews (2009): 10(7);e333 .
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, Dammann0, Allred EN J Pediatr 2010:157(5): 751-756.e1
Navarro, F & Gleason, WA, et al. NeoReviews (2009): 10(7);e333
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:
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–
–
–
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–
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1823 Billard describes first case of NEC
1850 Publication of a series of 25 term/preterm
First half of 20th 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.2012.12.012
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 23to 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.2012.12.012
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.2012.12.007
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.2012.12.007
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.2012.12.007
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
Lowest mortality
(29% [95% CI: 19–56]; P ,
.001)
* 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 IgA, IgM, IgG
Lactoferrin
Lysozyme
Complement C3
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
IgF 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.2010.01.013.
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.2010.01.013.
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
Formula + EBM*
100% EBM*
NEC Rate 7.2%
No BM used
NEC Rate 2.5%
When ANY EBM used
NEC Rate 1.2%
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
Schanler4
Sisk5
(2007)
Meinzen-Derr6
(2009)
Sullivan7
(2009)
McGuire3 (2007)
Schanler2
Lucas1
(1990)
(2003)
(1999)
•1Lucas,A.; Cole,T.J. Lancet 1990 (ii) 1519-1522
•2Schanler,Richard J; Hurst,Nancy M.; Lau,Chantal Clinics in Perinatology 1999 (26) 379-398
•3McGuire W & Anthony MY J Pediatr 2003 Jul;143(1): 137-8.
•4Schanler, RJ Am J Clin Nutr 2007 (85[SUPP]) 625s•5Sisk PM et al Journal of Perinatology (2007) 27, 428–433; doi:10.1038/sj.jp.7211758; published online 19 April 2007.
•6Meinzen-Derr J, et al. J Perinatol. 2009 Jan;29(1):57-62. Epub 2008 Aug 21
•7Sullivan S, Schanler RJ, Kim JH, et al. J Peds e- published 2009: DOI 10.1016/jpeds 2009-10.040
NEC: What Is The Emerging Evidence?
n=207 Preterm Infants BW ≤ 1250 g
ALL Received Their Mother’s Own Milk
Donor Milk
Preterm Formula
When OMM is not available
in sufficient quantity
When OMM is not available
in sufficient quantity
Human HMF
Human HMF
Bovine HMF
@ 100 mL/kg/d
@ 40 mL/kg/d
@100 mL/kg/d
H100 n=69
H40 n=71
B100 n=69
Study Protocol
Sullivan, S et al 10.1016/j.jpeds.2009.10.040
NEC: What Is The Emerging Evidence?
18
Incidence of Surgical NEC or
Death
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 mL/kg/d
HMF @ 40 mL/kg/d
Hum 100 + Hum 40
Bovine-Based Powdered HMF: @100 mL/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
Sullivan
2009
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
• Epithelial Cells
• Mucous
Secretions
• 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
• Epithelial Cells
• Mucous
Secretions
• 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
• Epithelial Cells
• Mucous
Secretions
• 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
• Epithelial Cells
• Mucous
Secretions
• 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.2012.12.002
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.2012.12.002 )
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.2012.12.009
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.2012.12.002
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.2012.12.002
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.2012.12.002
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:F147-F151.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:F147-F151.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:F147-F151.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
< 2kg
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:F147-F151.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 McCallie, HC Lee, O Mayer, RS Cohen, SR Hintz and WD
Rhine Journal of Perinatology (2011) 31, S61–S67.
• 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 & deKlerk N Arch Dis Child Fetal Neonatal Ed 2005; 90(2): F147-51
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
Feeding2
Probiotics
Use of
Feeding
Protocol1
Human Milk Feeding
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:
[email protected]