Best Practices: Improving Neonatal Outcomes through Exclusive Human Milk Jae Kim, MD, PhD Department of Pediatrics Division of Neonatal-Perinatal Medicine Division of Pediatric Gastroenterology, Hepatology and Nutrition CAPH Conference, Halifax, Oct 2016
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Oct 24 CAPHC Lunch Symposium - Sponsored by Prolacta - Dr. Jae Kim
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Best Practices: ImprovingNeonatal Outcomes through
Exclusive Human MilkJae Kim, MD, PhD
Department of PediatricsDivision of Neonatal-Perinatal Medicine
Division of Pediatric Gastroenterology, Hepatology and Nutrition
BIOLOGICS1. nucleotides 2. prebiotics (term formula only)3. probiotics (term formula only)
Benefits of mother’s milk to preterm infants• Cognitive development• Reduction in necrotizing enterocolitis (NEC)• Reduction in sepsis• Favorable alteration of microbiome• Reduction in retinopathy of prematurity (ROP)
• PLUS all the health benefits known for mother’ milk in term infants: reduction in infant mortality, SIDS, autism, ADHD, allergy, asthma, infection, celiac disease, cognitive outcomes, etc.
2016 March of Dimes Prematurity Report Card
Impact of Neonatology to Healthcare Burden• Between 7% (CAN) to 12% (US) of live births are preterm (less than 37
weeks gestation)• NICU patients (preterm and sick newborns) represent a
disproportionate share of hospital costs• Lifelong impact to healthcare burden and costs enormous• In the US, NICU is a top generator of financial revenue to hospitals
Morbidities of the preterm infant• Growth
• Impaired growth• Altered body composition• Failure to thrive
• Brain• Intracranial hemorrhage• Loss of white and gray matter, reduced size
• Cardiovascular• Effects of patent ductus arteriosus• Long-term risk of cardiovascular disease and metabolic
Provide nutrients to approximate the rate of growth and composition of weight gain for a normal fetus of the same post-conceptional age and to maintain normal concentrations of blood and tissue nutrients.
American Academy of Pediatrics Committee on Nutrition, In Pediatric Nutrition Handbook, 2013.
Matching In Utero Growth
Zeigler et al., Growth. 1976 Dec;40(4):329-41.
WEIGHT CLASS
GROWTHG/KG/DAY
~ 3 lbs per day for 70 kg adult
The Developing Gut1st Trimester 2nd Trimester 3rd Trimester
Adapted from Commare and Tappenden, 2007 Nut Clin Pract
Cytodifferentiation
Absorption
Motility
Digestion
Morphogenesis
Swallowing
0wk 14 22 28 40
ViabilityLine
STRU
CTU
REFU
NCT
ION
Preterm Risk Factors for Bowel Injury• Ischemia• Immature gut and systemic immune system• Dysmotility• Underdeveloped physical mucosal barrier (tight
Necrotizing Enterocolitis• NEC is the most common life-
threatening gastrointestinal emergency in the newborn period
• NEC is marked by intense inflammation and acute intestinal necrosis
• Most common sites include terminal ileum, cecum and ascending colon
The Perfect Storm for NEC
PREMATURITY ISCHEMIA PATHOGENIC BACTERIA
ENTERAL FEEDING
TRANSMURAL BOWEL
INFLAMMATION
BOWEL NECROSIS
BREAKDOWN OF MUCOSAL
BARRIER/DEFENSE
NEC Pathogenesis
Hunter et al. 2008 Pediatr Res 63;2:117
Pneumatosis Intestinalis
Coagulative Necrosis
NEC Morbidity• Growth failure due to bowel injury• Intestinal obstruction and subsequent surgery• Longer hospital stay• Risk of dying• Risk for more pain and suffering• Short bowel syndrome and/or intestinal failure
• Can lead to need for long-term PN use and later bowel transplantation
Cristafalo et al. J Pediatr. 2013 Dec;163(6):1592-1595.e1.
Exclusive human milk reduces overall NEC and surgical NEC
Sullivan et al (2010) J Pediatr. 2010;156:562-7
Protocol violations:received bovine product
Impact of choosing bovine products
No NEC Medical NEC Surgical NECMortality 10.6% 20.9% 23.2%
Double the risk of death!
Sullivan et al (2010) J Pediatr. 2010;156:562-7 Ganapathy et al. 2011 Breastfeeding Medicine
NEC continues to add to long-term costs within the first three years of life
• Texas Medicaid healthcare utilization database• Jan 2012 to Dec 2013• 253 survivors of NEC (73 surgical NEC)• 2909 matched controls• Medical NEC incurred higher costs than controls between 6 and 12
months• Surgical NEC incurred higher costs than controls up to 36 months
• Costs tapered down from ~ 18K to 8K per survivor
Ganapathy et al. BMC Pediatr. 2013 Aug 20;13:127.
An exclusive human milk (EHM) diet reduces TPN need
Ghandehari et al. BMC Res Notes. 2012 Apr 25;5:188.
11-14% Reduction in TPN useGreater when looking at TPN after initial use
Increased likelihood if HMF started earlier
EHM
Balance of effects in developing NEC
Benefit of
Human Milk
Detriment of
Formula
Decreased cost and improved feeding tolerance in VLBW infants fed an exclusive human milk diet• Retrospective study including preterm infants 28 weeks and/or VLBW ⩽
( 1500 g)⩽• Single center (The Herman & Walter Samuelson Children’s Hospital at Sinai,
Baltimore, MD, USA)• March 2009 until March 2014
• (2012-2014)• group H (exclusive human milk or EHM)
• (2009-2012)• group B (bovine-based fortifier and maternal milk)• group M (mixed combination of maternal milk, bovine-based fortifier and formula)• group F (formula fed infants)
• N = 293 infants between 23 to 34 weeks gestation and birth weights between 490 and 1700 g
Assad et al. J Perinatol. 2016 Mar;36(3):216-20.
Less feeding intolerance (P<0.0001)Lower number of days to full feeds by 9-10 days (P<0.001)Lower incidence of NEC (P<0.011)Shorter length of stay by 4 to 22 days for EHM groupSimilar average weight gain per among the four groups (18.5 to 20.6 g per day)
Assad et al. J Perinatol. 2016 Mar;36(3):216-20.
Lower total hospitalization costs by up to $106,968 per infant (P<0.004) in those fed an EHM diet
Assad et al. J Perinatol. 2016 Mar;36(3):216-20.
Beyond Necrotizing Enterocolitis Prevention: Improving Outcomes with an Exclusive Human Milk-Based Diet
• Retrospective cohort study• 4 centers, N =1,587 infants (Texas, Illinois, Florida, and California)• Lower NEC (16.7% versus 6.9%, p < 0.00001)• Reduced mortality (17.2% versus 13.6%, p = 0.04)• Reduced late-onset sepsis (30.3% versus 19.0%, p < 0.00001)• Reduced ROP (9% versus 5.2%, p = 0.003)• Reduced BPD (56.3% versus 47.7%, p = 0.0015)
Hair et al. Breastfeed Med. 2016 Mar;11:70-4.
Continuum of Health Benefits from Human Milk
Newborn SeniorChild
NEC Neurodevelopment
ROP Visual performance
BPD Asthma, Lung Disease, Neurodevelopment
Adult
Sepsis Neurodevelopment
Containing Health Care Costs• What motivates reduction in health care costs?
• Public model of cost-bundled that limit spending per patient (Medicaid)• Fee for service• Payer that pay out for sicker patients staying longer in hospital
• Performance or outcomes based incentives• Value based models• Perspective matters
• Cost to the patient and family• Cost to the hospital• Cost to the healthcare system• Cost to society
Economic Costs of NEC• One case of medical NEC is almost $75,000 USD• One case of surgical NEC is almost $200,000 USD
• NEC costs the health care system $5 billion USD annually (assume 10% incidence of NEC and 30% mortality)
• NEC constitutes 19% of the total costs for initial care for all newborns in the US
Bisquera J et al. Pediatrics 2002;109:423-428Ganapathy et al. Breastfeed Med. 2012 Feb;7(1):29-37
Balancing the cost of an exclusive human diet
Feeding of 160 mL/kg/dayPowder HMF: 1 packet per 25 mL of milk =$0.06/mL = 100X costs
Ganapathy et al. Breastfeed Med. 2012 Feb;7(1):29-37
Cost equation• Costs CAN 12,500 per patient• Protocol to 34 weeks according • Net savings of CAN 10,208 per patient given EHM diet
• If human milk was a drug, would we act differently?
Ganapathy et al. Breastfeed Med. 2012 Feb;7(1):29-37
History of Donor Milk
• 1909: the first milk bank was established in Vienna, Austria
• 1910: milk bank in Boston• North American history in milk banking is 100 years
old• 1974: Canada’s first milk bank in Vancouver• By early 1980’s 23 banks in Canada and 30
in US• 1981: HIV identified as a pathogen; North
America reduced to 8 banks• 1985: Human Milk Banking Association of North
America (HMBANA) established • 2000: Vancouver Milk Bank almost closes
Modern Human Milk Banking• HMBANA• International Human Milk Banking Association• Organizations in other countries
• UKAMB & other European countries• South America – Brazil & Venezuela• South Africa• Other countries – India, Japan, China
• National Milk Bank (est. 2005)• Prolacta Bioscience (est. 2005)• Medolac (est. 2013)
Donor Milk Banking in North America
hmbana.org
Existing Milk Banks Cities Served by Milk Banks
Donor human milk
PROS• Human specific• Bridges gap when
mother’s milk supply insufficient to meet infant’s requirements
CONS• Lower quality milk compared to fresh
milk• No cellular components or probiotics• Less protein due to maturity of milk• No lipase activity that may alter
digestion• Reduced bioactive components due
to processing• Reduced salts and vitamins
Screening(Questionnaire and Blood)
Expression of milk
Freezing, storage, andtransport
Thawing and Bacterial culture
Batching
Pasteurization
Culture of batch
Freezing
Processing of Donor Human Milk
Thawed for use
Mothers’ Own Milk Bank of Austin, Texas
HMBANANONPROFITMILK BANKING
COMMERCIAL MILK BANKING
Major Concerns For Use of Donor Human Milk
• Nutrition• Loss of bioactivity (immunologic protection)• Infectious risk• Tampering• Cost• Supply• Legal
Level of Quality of Human Milk
• Breastfeeding
• Fresh human milk
• Refrigerated human milk
• Really frozen human milk (-80ºC)
• Frozen human milk (-20ºC)
• Donor human milk
TRIAGE• Colostrum > Fresh mature >
Refrigerated > Frozen
Recommendations for Donor Human Milk Banking
AAP Committee on Nutrition Statement (in press)CPS Committee of Nutrition (Kim and Unger) 2012• Donor human milk is an acceptable alternative to mother’s own milk for preterm infants
when it is not available• HMBANA or commercial donor banks are suitable sources• AAP
• The use of donor human milk in appropriate high-risk infants should not be limited by an individual’s ability to pay.
• Policies are needed to provide high-risk infants access to donor human milk on the basis of documented medical necessity, not financial status.
• Avoid unpasteurized milk sharing off Internet
• CPS• Recognized functions of the human milk bank should include the promotion of breastfeeding and
ongoing human milk research.• Pasteurized human donor breast milk should only be prescribed following written informed
consent from a parent or guardian.
Canadian Milk Banking
California Milk Banking
MMB of San Diego 2017
• All of California is currently served by one milk bank
• UC San Diego is developing a milk bank in San Diego for Southern California
Benefits of Donor Human Milk to Preterm Infants
• DOMINO Study (Canada)• Recently completed• Saw reduction in NEC• Long-term followup data pending
• NICHD (Donor milk trial)• Ongoing recruitment• Slowing recruitment due to loss of equipoise
• Optimom study (Canada)• Donor milk derived fortifier study• Closed but not reported
Oral Colostrum CareOropharyngeal administration involves placing small amounts of a liquid directly onto the oral mucosa with expectation that the liquid, or any of its components, is absorbed by the mucous membranes.
Rodriguez, N.A., et al., Oropharyngeal administration of colostrum to extremely low birth weight infants: theoretical perspectives. J Perinatol, 2009. 29(1): p. 1-7.
Colostrum Breast MilkTotal Protein (g/100mL) 3.7 1.3
IL-6 (pg/mL) 978.8 86.92
Fat (g/100mL) 2.9 4.2
Lactose (g/100mL) 57 7.4
IgM (mg/g protein) 30 4
IgA (mg/g protein) 175 20
IgG (mg/g protein) 3 2
Colostrum• Produced when the tight junctions in the mammary epithelium are
open• Paracellular transport of immunologically derived protective components
from mother’s circulation into milk
• Contain various immunomodulatory agents • Secretory immunoglobulin A [sIgA]• Growth factors• Lactoferrin• Anti-inflammatory cytokines
• More highly concentrated in mother’s of preterm infants
Evidence that oral colostrum care benefits preterm babies
• Seigel 2013• Retrospective cohort study of 369 inborn ELBW infants, 5 day treatment• Mortality, surgical NEC, SIP rates unchanged• Higher weight at 36 weeks (1666g vs. 1380g p<0.001)
• Lee 2015• Double blind, placebo-controlled trial of 45 infants <28 weeks gestation in South Korea• Increased urine levels of immunoglobulin A and lactoferrin• Significant decrease in clinical sepsis
• Sohn 2016• Impact of buccal administration of human colostrum on the oral microbiota of 12 VLBW
infants• OCC altered the colonization of the oral cavity with effects lasting after the intervention
ELBW = birth weight less than 1000 grams; VLBW = birth weight less than 1500 grams
Human milk derivatives: value of a cream supplement
• HM-derived cream supplement if energy density of HM <20 kcal/oz using a near infrared HM analyzer
• Treated until 36 weeks PMA
• HM-derived cream should be considered an adjunctive supplement to an exclusive HM-based diet to improve growth rates in premature infants
Human Milk
HumanHMF
Exclusively Human
Human milk
cream
Velocity Cream supplemented(n=39)
No cream(n=39)
p
Weight (g/kg/d) 14.0 +/- 2.5 12.4 +/- 3.0 0.03
Length (cm/wk) 1.03 +/- 0.33 0.83 +/- 0.41 0.02
Terminology
MicrobiotaThe collection of microbes in a
particular environment
MicrobiomeThe catalog of microbes and their genes in a particular environment
MetagenomicsThe collection of genes and genomes from microbiota
Terminology
PROBIOTICS POSTBIOTICSPREBIOTICS
SYNBIOTICS
Human Milk is the Original Synbiotic
The human gastrointestinal microbiota
• First inoculation during birth with passage through birth canal
• Influenced by prebiotics and probiotics• Adult microflora by 2 years of age• Over 500 bacterial species• 1010 organisms (at least ten fold higher than
human cells)• Symbiosis between man and bacteria• 5-10 lbs of bacteria, about 60% of fecal mass• The “forgotten organ”
We need microbes!
N Engl J Med. 2002 Sep 19;347(12):911-20.
FALL OF INFECTION RISE OF AUTOIMMUNITY AND IMMUNE DYSFUNCTION
Dysbiosis
• sick ecosystem• low diversity of species• Imbalance• lack of functional redundancy• susceptibility to disease
Type of birth
Vaginal birth C-section• Sterile environment• Frequent use of antibiotics• Preterm infants born ~70% by C/S• Exposure to nosocomial microbes• Long-term risk of food allergy
• Papathoma et al. 2016
• Long-term risk of immune dysfunction• Asthma, laryngitis, gastroenteritis, ulcerative
Changing the clinical practice towards a dominant mother’s
milk culture in hospitals is very challenging but cost effective in promoting a
healthier long term outlook for premature infants
The future…
Exclusively Human
Human Milk
HumanHMF
Donor milk derived
additives
• Maternal lactation support• Donor human milk banking• Lacto-engineering science
• Addition of cream• Addition of protein• Human milk derivative bioactive additives
• Refinement of processing of human milk for preservation of function
• Increased cost benefit analysis for other long-term morbidities
Priorities1. Maternal lactation2. Donor human milk3. Human milk fortifiers4. Human milk derivatives
The SPIN Program Ten Steps
1. Have a NICU nutrition/human milk policy2. Educate all mother/baby staff in SPIN 10-steps3. Educate NICU families about optimal premature
infant nutrition4. Prevent extra-uterine growth restriction5. Standardize enteral feeding procedures6. Target 100% human milk nutrition 7. Maximize mothers’ milk production8. Optimize milk quality and safety9. Encourage skin-to-skin care and breastfeeding10. Plan a nutritional discharge from NICU
NUTRITION LACTATION
THE SPIN TEAM
• Medical director• Lactation director• NICU F/U Neo• NICU CNS• Lactation• OT• NICU Dietician• Research RN• NICU Staff RN
spinprogram.ucsd.edu
Take home points• Human milk is the single most powerful
intervention to optimize the best health outcomes in all babies
• In the absence of maternal milk, donor human milk is a superior substitute to formula
• Donor milk derivatives now support the provision of an exclusively human milk diet
• Initiating and maintaining a balanced gut microbiota begins with maternal milk
• Moving towards an exclusively human milk diet will show increasing cost savings and long-term healthcare benefits to preterm infants