LINEAR AND HEAD CIRCUMFERENCE GROWTH IN PREMATURE NEONATES RECEIVING FORTIFIED HUMAN MILK WITH SUPPLEMENTAL PROTEIN
Advisors: Sharon Foley, PhD, RD, LDN Celina Scala, MS, RD, LDN, CNSC
Committee Members: Yimin Chen, MS, RD, LDN, CNSC Aloka Patel, MD
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Xing Pan (Freida) B.S., University of Nebraska-Lincoln
o Definition • Infants born less than 37 weeks gestation • High risk for mortality 1
o Prevalence of premature infants in the U.S. • 11.54% in 2012 (The National Vital Statistics )2
o NICU: Neonatal Intensive Care Unit
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1 Stoll BJ et al, 2010;126(3):443-456. 2 Brady E et al, National Vital Statistics System. 2013;3.
o Growth restriction: • Due to inadequate postnatal nutrition delivery 1 • The 3rd trimester of pregnancy 2
• Highest accretion rate for Ca, phos, mg • Support normal growth and bone mineralization
• To assess: • Weight: baby scale • Linear growth: length board vs. tape measure • Head circumference: tape measure • Growth charts: Olsen vs. Fenton
o Protein needs • Help infants to reach normal growth rates 3
• Extremely Low Birth Weight (ELBW) infants: 3.8-4.4 g/kg/day 4 • Very Low Birth Weight (VLBW) infants: 3.4-4.2 g/kg/day 4
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1 Clark Ret al, 2003;111(5 Pt 1):986-990. 2AAP Committee H on Nutrition, 6th ed. ; 2009:79
3Dusick AM et al, 2003;27(4):302-310. 4 Tsang Reginald C , 2005:427.
o Human Milk (HM) • Maternal milk • Donor human milk
o Preterm Formula o Human Milk Fortifier (HMF) o Liquid Protein • Similac®, Liquid Protein Fortifier (Extensively Hydrolyzed
Protein), Abbott Laboratories, Abbott Park, IL 6
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PURPOSE • To determine if the addition of the new liquid
protein product to fortified human milk (defined as HM fortified with HMF) improves linear and head circumference growth in preterm infants.
o Preterm Mortality and Morbidity • Gestational age (GA) is closely associated with
mortality and morbidity rates 1
o Extrauterine growth restriction • Extrauterine growth restriction associated with low
birth weight and immature GA 2
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Clark et al (2003)2
N=24,371 preterm infants
Results
Extrauterine growth restriction (EGR) at discharge
EGR attributed to low GA and low BW (R 2)
• Weight restriction: 28% • Length restriction : 34% • Head circumference (HC) restriction: 16%
0.45 0.35 0.19
1 Stoll BJ et a, 2010;126(3):443-456. 2 Clark RH et al, 2003;111(5 Pt 1):986-990.
o Gestational age o Preterm: infant born at< 37 weeks gestation o Term: infant born at 37-42 weeks gestation o Post term: infant born at >42 weeks gestation
o Birth weight o Low birth weight (LBW): <2500 g o Very low birth weight (VLBW) <1500 g o Extremely low birth weight (ELBW): <1000 g
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o Human Milk (HM) • Maternal Milk • Donor Human Milk
o Formula o Human Milk Fortifier (HMF)
o Basic contents: mineral and protein supplements, with additional energy
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12 1 Gross SJ et al, 1981;99(3):389-393. 2 Patel AL et al, 2013;33(7):514-519. 3 Okamoto T et al, 2007;49(6):894-897. 4 Meinzen-Derr et al, 2009;29(1):57-62. 5 Cristofalo EA et al, 2013;163(6):1592-1595.e1. 6 Sullivan S et al, 2010;156(4):562-7.e1.
o HM provides • Antibodies and oligosaccharides that both help to
build immunity in early infancy 1
• Decreased risk of: • Sepsis 2, retinal detachment 3, and
necrotizing enterocolitis (NEC) 4-6
• Calcium and Phosphorus • Preterm needs:
• Calcium: 100-220 mg/kg/day 1
• Phosphorus:60-140 mg /kg/day 1
• Without an adequate supply of calcium and phosphorus, osteopenia and rickets are major concerns in preterm infants 2,3
• Human Milk Fortifier
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1 Tsang Reginald C, 2005:427. 2 AAP Committee on Nutrition, 2009:79. 3 American academy of pediatrics committee on nutrition, 1985;75(5):976-986.
o Basic composition: • Mineral supplements, with additional protein and
energy.
o Primary purpose: • Correct for the inadequate amount of minerals such as
calcium and phosphorus
o Standard practice
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• Protein • The concentration of protein is higher in the
preterm milk than the full term milk over the first 4 weeks of lactation 1
• Protein concentration: • Drops significantly in both term and preterm
milk with increased postnatal age3-6 • More pronounced decline in protein content for
preterm milk 3-6
• Narang et al (2006) • Tested the protein contents of preterm milk (PM)
and term milk (TM) during the first 28 days of lactation.
15 1 Narang AP et al, 2006;21(1):89-94. 2 Paul VK et al, 1997;64(3):379-382. 3 Faerk J et al, 2001;501:409-413. 4 Zachariassen G et al, 2013;60(6):A4631. 5 Atkinson SA et al, 1980;33(4):811-815. 6 Lucas A et al, 1984;59(9):831-836.
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o P1: preterm human milk sample (GA: <33 wks, n=22) o P2: preterm human milk sample (GA: 33-36 wks, n=23) o T1: term human milk sample (GA: 37-41 wks, n=41) o Total HM sample: n=334
11Narang AP et al, 2006;21(1):89-94.
Narang et al (2006)
o Holder pasteurization • 62.5°C for 30 minutes • To eliminates viral and bacterial contaminants
o Macronutrients contents • Fat and protein contents were lower in the donor milk 3
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1 Fidler N et al, 2001;501:485-495. 2 Goes HC et al, 2002;18(7-8):590-594. 3 Ntoumani E et al, 2013;89(4):241-244.
o Current recommendation 1 • ELBW infants: 3.8-4.4 g/kg/day • VLBW infants: 3.4-4.2 g/kg/day
o Required vs. Actual received • Arslanoglu et al (2009) 2
• The protein received by preterm infants fed with fortified HM was actually less than their required needs.
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Population Feeding Regimen
Assumed vs. Received
32 infants with birth weight between 600-1750 g and GA between 24 and 34 weeks
HM (own or donor)+HMF No formula was fed at any time
Assumed protein content of HM: 1.5 g/100 mL
Actual protein intake: bi-weekly analysis
1 Tsang Reginald C, 2012;26(3 Suppl):43-47. 2 Arslanoglu S et al, 2009;29(7):489-492.
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Study Sample size
Methods Growth outcomes
Results
Cooke et al (2006) 1
n=18
Cross-over design (2 one week) Standard formula • 1 week • Protein: 3.0 g/100 kcal • n=9 High protein formula • 1 week • Protein: 3.6 g/100 kcal • n=9
Weight gain (g/day)
HiPro formula: 35±9 g/d RegPro formula: 27±6 g/d p<0.005
1 Cooke R et al, 2006;59(2):265-270.
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Study Sample size
Methods Growth outcomes
Results
Cooke et al (2006) 1
n=18
RegPro group: standard formula • Protein: 3.0 g/100 kcal • n=9 HiPro group: high protein formula • Protein: 3.6 g/100 kcal • n=9
Weight gain (g/d)
HiPro formula: 35±9 g/d RegPro formula: 27±6 g/d p<0.005
Ernst et al (2003) 2
n=69 Infants were stratified by BW: • Group 1: ≤ 750 g (n=27) • Group 2: 751-1000 g (n=42)
Feeding methods including: • HM+HMF • HM+Formula Deficit of protein intake: calculated by subtracting actual daily intake from goals.
Weight gain HC
At discharge: • Group 1: 21.8 g/kg • Group 2: 7.8 g/kg
1 Cooke R et al, 2006;59(2):265-270. 2 Ernst KD et al, 2003;23(6):477-482.
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o Kuschel and Harding (2009) 1 • Meta-analysis study • Randomized or quasi-randomized controlled trials
• N=90 infants.
• Results:
• Adding protein to human milk had a positive effect on the short-term growth parameters:
• Increased weight gain (3.6 g/kg/day, 95% CI 2.4 to 4.8 g/kg/day)
• Increased linear growth (0.28 cm/week, 95% CI 0.18 to 0.38 cm/week)
• Increased head growth (0.15 cm/week, 95% CI 0.06 to 0.23 cm/week).
1 Kuschel CA and Harding JE, 2009;(2)(2):CD000433
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o Polberger et al (1989) 1 • Double-blind, randomized control study • Four weeks study • Infants were randomly assigned to:
1. HM (control group) (n=7) 2. HM+Human Milk Fat (n=7) 3. HM+ Human Milk Protein (n=7) 4. HM+Human Milk Fat+Human Milk Protein (n=7)
• Primary outcomes: • Weight (g/kg/d) • Length (cm/wk) • HC (cm/wk)
• Results • The protein intakes between four-week study ranged from 1.7 to 3.9 g/kg/d • Table
1 Polberger SK et al, 1989;25(4):414-419
o Index of brain growth • A strong predictor of adverse neurodevelopment
outcome especially at three months of age 1
o Measuring technique • Measuring tape
• “ The tape should be passed around the head, positioned just above the eyebrow ridges, above the ears and around the occipital prominence at the back of the head.” 2
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1 Neubauer V et al, . 2013;102(9):883-888. 2 Maclean A, ed. 1.0th ed. United Kindom: NHS Greater Glasgow and Clyde; 2008.
o Two commonly used techniques to obtain length information in the NICU are tape-measure and length-boards. o Tape-measure vs. Length-boards • Corkins et al 1
• Compared the accuracy of admission lengths for preterm infants obtained using a tape-measure vs. length-board technique
• Clifford et al 2 also found inconsistencies between two techniques • Unpublished study conducted at Rush University Medical Center • n=883 preterm infants • Mean difference between length board vs. tape measures: 0.45 ± 1.4 cm.
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Corkins et al (2002)
Population • Preterm infants • n=25
Methods o Inter- and intra-examiner agreement for length board was established using ICC
o Admission length was compared using both techniques (tape measure vs. length board)
Results o Length board: almost perfect agreement between raters (ICC~1.0) o Mean difference: -0.252 cm (95% CI:-1.562-1.058) (p=0.69)=NS o Mean absolute difference: 1.7 cm, with the tape measure higher than length-
board o % of difference of using length board vs. tape measure
o 84%: ≥ 0.5 cm o 64%: ≥ 1 cm
o When plotting length data on the weight-for-length growth curve:
o 13 of the 25 patients (52%) had a shift of their percentile range
1 Corkins MR et al, 2002;109(6):1108-1111. 2 Kerry Clifford et al, 2014, Rush University Medical Center
o Measuring technique • A baby gram scale 1
• Reliability • Weight measure is more reliable measurements than HC and
length measurements 2
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1 Maclean A, ed. 1.0th ed. United Kindom: NHS Greater Glasgow and Clyde; 2008.
2 Johnson TS et al, 1997;24(5):497-505.
Johnson et al 1
• Sample: n=50 term infants in a U.S. hospital • Methods:
• Weight: an electronic scale
• Head circumference: tape measure
• Length: tape measure • Each measurements was obtained on each infant twice by two
examiners
• Results
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1 Johnson TS et al, 1997;24(5):497-505.
Inter-examiner ( % of error )
Weight Set 1: 0.06 Set 2: 0.05
HC Set 1: 1.05 Set 2: 1.02
Length Set 1: 3.13 Set 2: 2.92
Intra-examiner ( % of error ) Weight
Examiner 1: 0.06 Examiner 2: 0.10
HC Examiner 1: 0.83 Examiner 2: 0.83
Length Examiner 1: 1.86 Examiner 2: 2.35
o Fenton growth chart 2013 1 • Gender specific • From 22 weeks GA to 50 weeks GA • Harmonized with the WHO Growth Standard at 50 weeks (support nice transition
of preterm growth to WHO charts) • Limitation: not specific to the U.S. infants
o Olsen growth chart 2 • Created in 2010 • Based on a cross-sectional sample of infants
• N=257, 855 infants who survived to discharge (1998-2006) • 23 to 41 weeks’ GA. • 248 hospitals within 33 U.S. state
• Curve creation and validation • Weight-, length-, and HC-for-age growth curves were created in the study
• Advantages • Gender specific • Compare to Fenton growth chart, more representative of the current U.S.
population, which is also ethnically diversified
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1 Fenton TR and Kim JH, 2013;13:59-2431-13-59.
2 2 Olsen IE et al, 2010;125(2):e214-24.
o To determine if there is a difference in linear growth and head circumference in neonates that receive additional liquid protein with fortified human milk (HM) vs. those that receive fortified HM only. o To determine if there is an association between
change in length percentiles and head circumference percentiles on the growth charts in neonates that receive additional liquid protein with fortified human milk (HM) vs. those that receive fortified HM only.
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o Research design • Retrospective, observational study using matched
historical controls o Setting • Neonatal Intensive Care Unit at Rush University
Medical Center, Chicago, IL o IRB approval • Expedited IRB approval has been obtained 31
o Accessible population • Preterm infants in the NICU at Rush University
Medical Center, Chicago, IL
o Selection • Non-probability, convenience sampling method
o Sample size • Power analysis 1
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1 O'Connor DL et al, 2008;121(4):766-776
o α = 0.05 (two-tailed) o β = 0.20 o Power = 0.80 o Mean (SD) length (cm) at 4 wk: • Treatment Group = 51.2 cm ( 2.5) • Control Group = 49.6 cm (2.9)
o Effect size: 0.59 o Number of Subjects per group = 46 o Total Subjects needed: 92
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1 O'Connor DL et al, 2008;121(4):766-776
Inclusion Criteria o Preterm infants (GA<37 wks)
o Received >50% of feeds as HM
o BUN < 8 on 2 consecutive
measurements, or • Linear growth ê below their
birth length percentile o Received liquid protein for ≥21 days • Similac® liquid protein fortifier
Exclusion Criteria o Term infants (≥37 wks) o Received ≤50% of feeds as HM o Born with serious congenital
anomalies, osteogenesis imperfecta and inborn error of metabolism that could affect growth
o Necrotizing enterocolitis, severe
birth asphyxia, and/or chromosomal aberrations
o Received liquid protein <21 days.
o Received 27 and 30 kcal formulas
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List from the NICU dietitian
Review EPIC to determine
eligibility
Liquid protein group: Infant A
Historical control group list from the
NICU secretary
Matching Process
1st step: Gender 2nd step: Gestational age 3rd step: Birth weight
Matched with infant a, b, c, d,
e, f
Matched with infant a Pair 1: Infant A+ Infant a
Matching Process
4th: GA when initiation of the feeding regimen 5th: Percent and type of formula received
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Historical Control Group
>50% HM/Donor HM HMF
≤50% Formula
Liquid Protein Group
>50% HM/Donor HM HMF
≤50% Formula
≤50% Formula
Liquid Protein
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Infant C
Day 1: length board/measuring tape Day 21: length board/measuring tape
Infant B
Day 1: length board/measuring tape Day 21: measuring tape
Historical control group Infants a ,b, c
Measuring tape
Liquid protein group Infant A
Day 1: measuring tape Day 21: length board/measuring tape
Demographic and Clinical Data
o Gender o Gestational age o Type of feeding o Mean energy intake (kcal/kg/
day) o Mean protein intake (kg/day) o Duration of feeding (number of
days) o Repeated BUN measures (mg/
dL) ) o Type of linear growth
measuring tools (tape or length board)
Anthropometrics Data
o Birth weight (g), length at birth (cm), HC at birth (cm)
o Repeated weight (g), length (cm) and head circumference (cm) measures
o Percentile of length, and percentile of HC
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o Statistical Package for the Social Sciences (SPSS) Statistical Package version 19.0 will be used for the analysis of all statistical information.
o A P-value< 0.05 will be considered significant o Normal distribution across all variables will be examined
o Medians and nonparametric alternative tests will be used if variables are not normally distributed
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o Descriptive statistics will be used to summarize demographic and clinical variables • Gender • Gestational age • Type of feeding • Mean energy intake (kcal/kg/day) • Mean protein intake (kg/day) • Duration of feeding (number of days) • Repeated BUN measures (mg/dL) • Type of linear growth measuring tools (tape or length board)
o Categorical data will be reported in frequency o Continuous data will be described using means or medians if not
normally distributed o Change in length and HC percentile from beginning to end of study will
be categorized and reported as a decrease, maintenance/increase in percentile.
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o Objective 1 • To determine if there is a difference in linear growth
and head circumference (HC) in neonates that receive additional liquid protein with fortified human milk (HM) vs. those that receive fortified HM only.
• A paired-t test will be used to determine if there is a difference
within groups and between pairs.
• Wilcoxon signed rank will be used if the data is not normally distributed.
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o Objective 2 • To determine if there is an association between
change in length/head circumference percentiles on the growth chart in neonates that receive additional liquid protein with fortified human milk (HM) vs. those that receive fortified HM only.
• Chi-squared test: determine the association between type of feeding
and change length/HC percentile (increase/maintenance vs. decrease from birth percentile category).
o .
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Thesis Proposal
• August, 2014
Data Collection
• August, 2014-January, 2015
Data Analysis • January, 2015-February, 2015
Thesis-Write-Up
• February,2015-March, 2015
Thesis Defense
• April, 2015
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