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Steven Abrams, MD

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Objective: Understand basis of regulation of infant formula ... Bier, J Perinatol 2002;22:354-359. BW 1.2 kg BW 1.2 kg. GA 29 wk GA 29 wk. DC 60 days DC 51 days ... – PowerPoint PPT presentation

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Title: Steven Abrams, MD


1
Infant formula safety and the safety and efficacy
of donor human milk
  • Steven Abrams, MD
  • Professor of Pediatrics
  • USDA/ARS CNRC
  • 1100 Bates St.
  • Houston TX 77030
  • Ph713-798-7124 FAX 713-798-7119
  • sabrams_at_bcm.edu

2
Overview and objectives
  • Infant formula safety
  • Objective Understand basis of regulation of
    infant formula content in US
  • Objective Recognize rationale for concern
    regarding infectious risks of infant formulas and
    methods of limiting these risks
  • Banked donor human milk
  • Objective Recognize rationale for the use of
    banked donor human milk for at-risk infants
  • Objective Understand methods of assuring safety
    of these products
  • Objective Recognize areas of ongoing research

3
Case study Missing formula components
  • In Oct. 2003 three infants were hospitalized in
    Israel within a week of each other with
    encephalopathy.
  • In Nov. 2003, a 5.5-month-old infant was admitted
    to a medical center in Israel with nystagmus and
    vomiting.
  • Infant was treated with thiamine and improved
    within hours.
  • All had been receiving the same soy-based
    formula. Ultimately the use of this formula in
    Israel resulted in 2 deaths and 13 additional
    hospitalizations.
  • The formula was found to have 1/10 the labeled
    amount of thiamine (29-37µg vitamin B-1 per 100 g
    formula vs. the labeled 385 µg per 100 g).

Siegel-Itzkovich , BMJ, 2003
4
Recent recall (Sept. 2006)
5
Also…
6
Assurance of nutritional adequacy of infant
formulas in the US
  • Requirements for nutrients in infant formulas are
    established by the FDA in the Federal Food, Drug,
    and Cosmetic Act.
  • Nutrient specifications include minimum amounts
    for 29 nutrients and maximum amounts for 9 of
    those nutrients.

http//www.fda.gov/opacom/laws/fdcact/fdcact4.htm
7
Assurance of nutritional adequacy of infant
formulas in the US
  • If formula does not contain nutrients at or above
    minimum level or within range, it is considered
    an adulterated product unless the formula is
    "exempt" from certain nutrient requirements.
  • Manufacturer analyze representative samples for
    all nutrients at least every 3 mo.
  • Manufacturers must notify FDA after processing or
    formulation changes as well as for new
    formulations.
  • Regulations for infant formulas last revised in
    1985.
  • Infant Formula Evaluating the Safety of New
    Ingredients (NAS, 2004). Process for evaluating
    new ingredients suggested. Decision tree analysis
    proposed for new ingredients.

http//www.fda.gov/opacom/laws/fdcact/fdcact4.htm
and http//www.cfsan.fda.gov/lrd/cfr106.html
8
Dont forget to keep the government and the
public informed!
The food company Nutricia has been warned by
food authorities in Australia and New Zealand
that they may have breached the Australia New
Zealand Food Standards Code by placing infant
formulas on the market before receiving necessary
approvals. While the Authority is not aware
of any evidence that the Nutricia products
containing FOS are unsafe, the products have not
been through the Food Standards Australia New
Zealand (FSANZ) approval process which includes
a safety assessment. FOS is permitted
within prescribed limits in infant formula sold
within the European Union. Products identical to
Nutricia Karicare Gold Plus Infant and Follow-On
formulas have been sold in Europe since 2000 with
no known health issues among babies or infants.
These products have been on sale in Australia
since January 2007 and NSW Health is not aware of
any reported problems. Nutricia have been
informed that they should have sought express
permission from Food Standards Australia New
Zealand (FSANZ) before adding any unapproved
nutritive substance to their infant formulas.
http//www.foodauthority.nsw.gov.au/advice-to-pare
nts-and-caregivers-nutricia.asp
9
Enterobacter sakazakii Case Study
  • A 1.3 kg infant was delivered at 33 wks via
    c-section.
  • DOL 11 - fever, tachycardia, and possible
    seizures
  • CSF culture grew E. sakazakii - infant died.
  • Additional suspected cases (tracheal
    colonization) and non-symptomatic infants in same
    NICU.
  • Single batch of a specific powdered infant
    formula product (Portagen) was found to be
    significantly associated with E. sakazakii
    infection or colonization
  • Opened and unopened cases from a single batch of
    Portagen grew E. sakazakii.

Morbidity and Mortality Weekly Report, CDC, 2002
10
Epidemiology
  • E. sakazakii implicated in 1958 in 2 cases of
    neonatal meningitis in England.
  • Worldwide, since 1958 there have been 70
    reported cases (24 deaths) of E. sakazakii
    infection believed acquired via powdered infant
    formula.
  • Full-term infants lt28 days (meningitis),
    premature infants (sepsis) are at greatest risk.
  • Reported mortality rates between 33-80.
  • Muytjens (1990) examined 141 different infant
    formulas from 35 different countries and isolated
    E. sakazakii from 20 formula samples from 13
    countries.
  • Current Codex Alimentarius Commission
    specifications for E. sakazakii permit 1-10
    CFU/gram of powdered infant formula.

Drudy , CID, 2006 Gurtler Int J Food Microbiol,
2005
11
E. sakazakii cases
Drudy et al., CID, 2006 Gurtler et al., Int J
Food Microbiol, 2005 Boween and Braden, Emerging
Infectious Diseases 2006121185.
12
General guidelines for the reconstitution of
powdered infant formula (PIF) in hospitals
  • PIF should have clear indication for use.
  • Personnel should use aseptic techniques to
    prepare PIF.
  • The use of sterile liquid formula is encouraged
    for healthy newborns. Single-use bottles,
    nipples, feeders recommended. All mixing
    utensils, bottles, and nipples should be
    disinfected
  • Formula prepared in advance should be done daily,
    and should be kept at lt 4C and discarded if not
    used in 24 hours.
  • Hang time for continuous feeds should be not
    over 4 hours. Intermittent feedings should be
    prepared as a single feeding.

Drudy et al., CID, 2006 Gurtler et al, Int J
Food Microbiol, 2005, ADA 2002.
13
General guidelines for the reconstitution of
powdered infant formula (PIF) in homes
  • Families of high-risk, formula-fed infants should
    be alerted that PIF is not a sterile product and
    encouraged to use liquid formula when possible.
  • Inactivation of E. sakazakii in infant formula
    will occur at temperatures 60C or higher.
  • European society (ESPGAN) recommends against this
    due to potential nutrient loss. Use of water at
    this temperature has not been included in US or
    TCH guidelines.
  • Detailed specific guidelines for
    high-risk/preterm infants do not exist. Limit PIF
    through 44 weeks PMA?

Agostoni et al, J Pediatr Gastroenterol Nutr,
2004 Drudy et al., CID, 2006 Gurtler et al, Int
J Food Microbiol, 2005
14
Boiling - effects on nutrients
No meaningful changes for Vit A, D,E,K,B1,B2,B6
Per label tap water boiled, cooled to 40C then
added and shaken. Boiling water boiled water
put into bottle and power added immediately.
  • http//www.fao.org/ag/agn/jemra/enterobacter_en.st
    m

15
Guides for parents
http//www2.texaschildrenshospital.org/internetart
icles/uploadedfiles/142.pdf
16
Safety and efficacy of using banked human milk in
the hospital setting
17
Outline
  • Background and potential benefits to human milk
    banking using own mothers milk (OMM) or donor
    milk (DM) in a high-risk population.
  • Guidelines for donor human milk banking
  • Safety Procedures
  • Potential limitations
  • Clinical Evidence
  • Conclusions

18
Benefits of human milk for at-risk infants
  • There are many well-recognized benefits of human
    milk for term, and (when fortified), premature
    infants
  • Fortified human milk provides nutrients with high
    bioavailability and supports optimal growth
  • Human milk reduces incidence and severity of
    infections, especially necrotizing enterocolitis.
  • Human milk-fed infants have a lower incidence of
    atopic disease and possibly other chronic
    illnesses.
  • Infants fed human milk tend to have improved
    development, especially, preterm infants
  • Despite advances in infant formula, human milk is
    the optimal nutrient source for nearly all
    infants.

AAP. Pediatrics, 2005115496-506.
19
Bioactive factors in human milk Food for the
brain protection for the GI Tract
  • Secretory IgA
  • Lactoferrin
  • Enzymes (e.g., PAF-acetylhydrolase)
  • Cytokines (e.g., IL-10)
  • Growth factors (e.g., EGF)
  • Nucleotides
  • Oligosaccharides
  • Antioxidants
  • Glutamine
  • Polyunsaturated fatty acids
  • Micronutrients

Hamosh M. Pediatric Clin No Amer 20014869
20
Necrotizing enterocolitis in preterm infants (UK)
In-Hospital Diet All Cases Confirmed Cases
Formulas Only (n236) 24 (10.2) 17
(7.2) Formulas plus Mothers Milk (n437) 16
(3.7) 11 (2.5) Human Milk (n 253) 11 (4.3) 3
(1.2)
OR Formulas only vs Human Milk only all cases
2.5 (1.25.2), plt0.02 confirmed 6.5 (1.922),
plt0.001 OR Formulas only vs Formulas as
supplements to Mothers Milk all cases 3.0
(1.55.7), plt0.005 confirmed 3.0 (1.46.5),
plt0.005 Multi-center Not randomized Human Milk
Mothers own milk and/or pasteurized donor milk
Lucas Cole, Lancet 19903361519-23
21
Survival Curves for NEC or death by amount of
human milk (ml/kg/d)
1.00
100 ml
0.95
Survival
50 ml
Estimate
0.90
20 ml
10 ml
0.85
0 ml
For NEC or Death after 14 days, adjusted for
birth weight, race, PDA treatment, ventilation,
and site Meinzen-Derr, et al NICHD Neonatal
Network. Presented SPR 2006
0.80
0
10
20
30
40
50
60
70
80
90
100
110
120
Postnatal age (d)
22
Effect of human milk on URI symptoms in preterm
infants during first year
Human Milk
Formula
BW 1.2 kg BW 1.2 kg GA 29 wk GA 29 wk DC 60
days DC 51 days
60
Cumulative URI Days (mean)

40

20


0
From discharge to
1 mo
3 mo
7 mo
12 mo
Human Milk (any)
100 71 29 10
Bier, J Perinatol 200222354-359
23
Human milk and subsequent intellectual
performance in premature infants at 8 y
Significant factors affecting IQ
Social Class - 3.5/class Mothers Education
2.0/group Female Gender 4.2 Mechanical
Ventilation - 2.6/week Receipt of Human Milk
8.3 IQ points
Lucas, Lancet 1992339261
24

Outcomes by quintiles of breast milk intake in
extremely premature infants
Breast Milk Percentile
None ? 20th 20- 40- 60- gt 80th
40th 60th 80th

Breast milk, mL/kg/d 0 1 7 24 64 111 DC on
breast milk () 0 1 2 9 40 85 Mean MDI
score _at_ 18 mo 76 74 77 78 80 87a Mean PDI score
_at_ 18 mo 81 81 83 84 84 89a Mean BRS ile _at_ 18
mo 46 45 52 50 52 59a Re-hospitalization lt1y
() 30 25 32 26 23 13a
Vohr, (Neonatal Newtwork) PEDIATRICS 2006 118
e115 avalue significantly different from
None Bayley Scales of Infant Development II
N775 Breastmilk (75) 260 No Breastmilk (25)
A. MDI, Mental Development Index Birth
weight 800 g Gestational age 27 wk B. PDI,
Psychomotor Development Index C. BRS, Behavior
Rating Scale
Co-variates Mat age, education, marital
status,race, GA, gender, infection, IVH, PVL,
BPD, NEC, weight
25
Magnitude of breast milk effect
  • For every 10 mL/kg/day ? breast milk intake
  • MDI ? 0.5 pts
  • PDI ? 0.6 pts
  • Behavior Rating Scale percentile score ? 0.8 pts
  • Re-hospitalization rate ? 6
  • For the highest quintile, an intake of 100
    mL/kg/day
  • ? 5 pts on MDI

Vohr, PEDIATRICS 2006 118 e115. Hack, NEJM
2002 346149
26
Effect of predominant mothers milk feeding on
late onset sepsis (LOS) and necrotizing
enterocolitis (NEC) in premature infants
Preterm Formula
50
50
Mothers Milk
45
45
Fortified Mothers Milk gt50 mL/kg/day
40
40
  • LOS/NEC p lt 0.01
  • Schanler, PEDIATRICS 19991031150

35
35
Infants
30
30
25
25
20
20
15
15
10
10
5
5
0
0
Late onset Necrotizing sepsis
enterocolitis
27
Human milk fortification
  • A response to the need to provide additional
    nutrients, especially minerals, for premature
    infants
  • Protein
  • Calcium
  • Phosphorus
  • Zinc
  • Used for most infants lt 1.8 -2.0 kg
  • Fortifiers available
  • Similac Human Milk Fortifier (Ross)
  • Enfamil Human Milk Fortifier (Mead Johnson)

28
Incremental effect of fortification
100
600
90
Increase over Unfortified HM
Increase over Unfortified HM
80
70
400
60
50
40
200
30
20
10
0
0
Ca P Zn Vitamins
Energy Protein Na Fat CHO
29
Fortified vs unfortified human milk
  • gt 600 infants randomized
  • Growth
  • Weight gain (g/kg/d) 3.6 2.74.6
  • Length (cm/wk) 0.12 0.07 0.18
  • Head circumference (cm/wk) 0.12 0.07 0.16
  • Bone mineral content (mg/cm) 8.3 3.8 12.8
  • Nitrogen balance (mg/kg/d) 66 35 97
  • BUN (mg/dL) 16 8 24
  • Relative Risk
  • Feeding intolerance 2.9 0.6 13 NS
  • Necrotizing enterocolitis 1.3 0.7 2.5 NS
  • Death 1.5 0.7 3.3 NS

Kuschel CA Harding JE 2005 The Cochrane
Library Some comparisons with partial
supplements
30
Donor human milk
  • Has the benefit of providing species-specific
    passive immunity.
  • Protection against necrotizing enterocolitis in
    premature infants (Mcguire W, 2003).
  • Offers minimal risk of feeding intolerance.
  • Has been used for infants with metabolic
    disorders, chronic renal failure, failure to
    thrive, and short gut syndrome.
  • Sources are non-commercial and commercial milk
    banks.

31
Donor milk banks Non-commercial
www.hmbana.org
1 Canadian and 10 US milk banks belong to the
Human Milk Banking Association of North America
(HMBANA).
32
Guidelines for donor milk banking in the US
  • As members, all voluntarily follow the Guidelines
    for the Establishment and Operation of a Donor
    Human Milk Bank, generated by HMBANA.
  • Guidelines include protocols for soliciting
    donors and collecting, processing and
    distributing milk.
  • All donors screened for antibodies to HIV-1,
    HIV-2, HTLV-1, HTLV-2, HBs Ag, Hep C, and
    syphilis.
  • Donors must also provide a full health and risk
    history and PPD if appropriate.

33
Tully, J Hum Lact, 200218393-6.
Donor milk supply and costs
  • Donor milk is dispensed either on hospital
    purchase order or physician order for a baby not
    hospitalized.
  • Donor milk banks are non-profit. All milk is
    donated.
  • Cost associated with donor screening and milk
    processing is offset by a processing fee
    (3.50/oz in the US for HMBANA milk) which is
    usually paid by the ordering institution or the
    recipient. Some insurance policies cover this.

34
Donor qualifications
35
Commercial donor milk bank
  • Milk donations obtained from healthy donors (not
    paid) after medical history. Donor is screened
    for markers to HBV, HCV, HIV-1 and 2, HLTV-1 and
    2, and syphilis. The milk is matched with the
    donor using DNA fingerprinting.
  • Each lot of milk is screened for the presence of
    bacterial contamination, drugs, and non-human
    proteins.
  • A sample analyzed for calories and
    macronutrients. Milk is either centrifuged to
    separate the fat or ultra-filtrated to
    concentrate proteins. The skim and cream are
    blended to bring the milk macronutrients to
    target levels.

36
Commercial milk banking procedures
  • Milk is pasteurized using a High Temp Short Time
    (HTST) process (standard temp 57C-72C).
  • After pasteurization, milk is stored at -30C.
  • Pathogen log-reduction of HIV is gt 7.3
  • Similar results for other bacteria and viruses
  • Methods similar to those used in preparation of
    human blood products.

37
Donor milk banking Efficacy?
38
Efficacy of donor milk Effects of pasteurization
Source commercial donor milk company
39
NEC and donor milk Meta-analyses
RR 0.2595 CI 0.06 to 0.98. McGuire Arch Dis
Child Fetal Neonatal Ed 2003
  • Another recent meta-analyses, using data from gt
    20 yrs ago found virtually identical results (RR
    0.21 95 CI 0.06 to 0.76). Boyd et al. Arch Dis
    Child. Fetal Neonatal Ed. Published online April
    5, 2006.

40
NEC and donor milk if include recent study
Morales and Schanler. Sem Perinatol 20073183-8.
41
Trial comparing mothers milk, donor milk or
formula Recent study
  • Randomized, blinded trial comparing
    infection-related events among extremely preterm
    infants fed mothers milk, donor human milk, or
    preterm formula
  • Infants lt30 weeks gestation were randomly
    assigned to receive pasteurized donor milk or
    preterm formula if their own supply of mothers
    milk became insufficient during the study

Schanler, et al., Pediatrics, 2005116400-6.
42
Results
  • No differences between group DM and group PF in
    incidence of infection related events, duration
    of hospital stay, or number of deaths. Compared
    with groups DM and PF, MM had fewer infection
    related events, and shorter hospital stay.

Schanler, et al., Pediatrics, 2005116400-6.
43
Conclusions
  • Limitations
  • DM and preterm formula groups received up to half
    their OMM which may have obscured differences.
    21 of infants switched over from donor milk to
    preterm formula.
  • Study not powered to detect differences in NEC.
    Incidence of NEC was much lower than pre-study
    expectation.
  • Conclusions
  • Larger studies are needed to determine benefits
    of donor human milk. Ideal comparison donor
    human milk vs preterm formula in infants who
    never received OMM.
  • However, providing donor milk to infants whod
    previously received human milk did not improve
    outcome relative to infant formula when OMM was
    no longer available.
  • Potential cost savings to banked human milk, if
    decreases incidence of NEC (not tested here),
    would be considerable.

44
Donor milk and formula nutrient contents
Component Donor Formula HM (per dL)
Milk Comm-fortifier
Energy (kcal) 60 87 87 Fat (g) 2.2 4.0 3.8 Prote
in (g) 1.1 2.2 2.2 Na (mEq) 0.6 1.5 1.3 Ca
(mg) 26 78 73 P (mg) 11 45 39
Donor Milk Banked, pooled donor milk, not
pasteurized. Tyson, J. Pediatr 1983 10395
www.prolacta.com
45
Donor milk conclusions
  • Most studies gt 20 years old and larger babies
  • Most donor milk was pasteurized removing most
    immunologically-active components. This is less
    true now.
  • NEC, sepsis not primary outcomes/not powered for
    these. Newer products can be adapted to higher
    nutrient intakes
  • It is currently difficult to evaluate benefits of
    banked HM. Key outcome variables of feeding
    tolerance and decreasing risk of NEC require
    large multi-center studies.
  • Evidence of safety is excellent
  • Cost-benefit analysis is difficult at this time
    until more data are available Currently, donor
    human milk is inadequately addressed in public
    health policy.

46
Objectives revisited
  • Infant formula safety
  • Objective Understand basis of regulation of
    infant formula content in US.
  • Objective Recognize rationale for concern
    regarding infectious risks of infant formulas and
    methods of limiting these risks
  • Banked human milk
  • Objective Recognize rationale for the use of
    banked human milk for at-risk infants
  • Objective Understand methods of assuring safety
    of these products
  • Objective Recognize areas of ongoing research so
    as to be able to follow this rapidly-developing
    topic

47
Thanks
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