Copyright Rush Mothers' Milk Club, 2011. · 2017. 8. 24. · Jeurink et al. Human milk: a source of...

Copyright Rush Mothers' Milk Club, 2011. All rights reserved. 1

Paula P. Meier, RN, PhD, FAAN Director for Clinical Research and Lactation

Neonatal Intensive Care And

Professor of Women, Children and Family Nursing And

Professor of Pediatrics Rush University Medical Center

Past President, International Society for Research in Human Milk and Lactation

www.isrhml.net www.rushmothersmilkclub.com

•  NIH: Health Outcomes and Cost of Human Milk Feedings for VLBW Infants (2007-2013).

•  AHRQ: Accelerating Comparative Effectiveness Research for Premature Infants (2010-2013).

•  Medela, Inc. Increasing Effectiveness, Efficiency, Comfort and Convenience of Milk Removal for Breast Pump-Dependent Mothers with Premature Infants

•  Anne and Kenneth Griffin Foundation •  Rossman Family Foundation •  Rush Women’s Board

Mammalian lactation patterns and milk composition have evolved over millions of years to support the survival,

growth, and development of mammalian offspring

• Largest brain of all mammals

• Because the brain is large, the head is large

• If the human fetus were to remain in utero and reach the maturity of other mammals, the head would be too large for normal delivery

• Thus, the human is the most “immature” of all mammals at the time of term birth

• Grow the human body slowly

• Lowest protein of all mammalian milk

• Grow the human brain rapidly in a highly specific manner

• High lactose and triglycerides for energy • Uniquely concentrated fats that facilitate optimal structural development and myelinization

• Protect, develop and program many body systems through synergistic functions: immunomodulatory, anti-inflammatory, gut-colonizing, and epigenetic mechanisms Kapellou et al., 2006

Brain Growth and Development Most Rapid During Last Trimester of Pregnancy

White Matter Microstructure at Term Corrected Age in Very Preterm (< 30 wks) Infants

Predicts Neurodevelopmental Outcome at 7 Years of Age

Thompson et al., Cortex 52: 60-74: 2014

Infection-Induced Inflammation and Cerebral Injury in Preterm

Infants

Strunk et al., Lancet Infectious Disease 2014; 14: 651-62.


Deoni et al., NeuroImage, 2013, 77-86

Breastfeeding and Early White Matter Development

•  133 Term Infants followed with neuroimaging and neurodevelopmental testing from 10 months-4 years of age

•  Relationship between duration of breastfeeding, white matter microstructure, and neurodevelopmental testing

Rush University Medical Center, Chicago

•  Regional perinatal center responsible for 25,000 live births

•  72-bed NICU •  Family-centered care

•  24-hour visitation •  Care by parent •  Parents attend medical

rounds

• Imbedded in the NICU is the lactation/human milk feeding program

• Practice: Families receive state-of-the art, evidence-based lactation care by the entire NICU staff

• Research: Families and infants serve as subjects in the team’s internally and externally funded research projects


Initial Visits to New Mothers Take about 1 Hour

Each BPC Maintains a Photo Album of Her or His NICU Baby from Birth through Current

Age

Discussion focuses on

impact of human milk on the

infant’s outcome

BPCs assist with

the first pumping session for all new

NICU mothers

• Proper use of the pump is taught • Breast shield sizing is done • Pump hygiene is reviewed • Pump rental is organized

Beverly Rossman, PhD, RN

Weekly Mothers’ Milk Club Luncheons Provide a Forum to “Share the Science” about Human Milk and Lactation


Helping Mothers Establish and Maintain an Abundant Milk Supply is a Major NICU Priority

Helping a new mother use the breast pump at her baby’s bedside in the NICU

Mother of a 24 week baby at the time of NICU discharge with 12 of the total 22 bags of extra milk she has pumped and stored

The Rush Mothers’ Milk Club breastfeeding peer counselors shipping 273 kilograms of pumped milk to a piglet laboratory for research purposes

Initiation

Coming to Volume

Maintenance

•  Profound hormonal, anatomical and milk composition changes

•  Mammary gland transitions from “preparing to make milk” (secretory differentiation) to “synthesizing and secreting milk (secretory activation, lactogenesis II)

•  “One-time event that is either achieved or not achieved

•  Interference impacts the “initiation of lactation”, not “the milk supply”

Progesterone

Prolactin

Lactogenesis II

Lactogenesis I

Neville & Morton. Physiology and endocrine changes underlying human lactogenesis II. J

Nutr 131: 3005S-3008S, 2001

mLs

per

day

Early Initiation

J Perinatology, 32: 205-209, 2012

Coming to Volume: Mechanisms and Best Practices

FIL

•  Period between the onset of lactogenesis II and achieving a threshold milk volume that is sufficient to maintain lactation

•  Autocrine control of lactation begins

•  Milk must be removed effectively and efficiently in order to be replaced

•  Problems that interfere with milk removal can have a long-lasting impact on lactation performance


Pumping Begins

Prolactin concentration increases 2-3 times over Baseline (more rapid milk

synthesis)

If available milk is not removed, the feedback inhibitor of lactation (FIL) works at the level of the individual breast to down- regulate milk synthesis

FIL

Knight, Peaker , Wilde. Local control of mammary development and function. J

Reproduction and Fertility 1998;3: 104-112

Evidence to Practice: Coming to Volume is a critical period, so it should be approached

proactively and interventions during this time should be given funding priority

Every mother is seen every day during this period to ensure milk expression is progressing optimally

Nutrition Begins Pre-Birth with the Swallowing of Amniotic Fluid in Utero

Sangild. Gut responses to enteral nutrition in preterm infants and animals. Exp Biol Med 231: 1695-1711, 2006. Sangild et al. Prenatal development of gastrointestinal function in the pig and the effects of fetal esophageal obstruction. Pediatr Res 52: 416-424,2002. Underwood, Gilbert, Sherman. Amniotic fluid: Not just fetal urine anymore. J Perinatol 25: 341-348, 2005

Last Trimester in Utero

• High concentrations of growth factors target the GIT epithelial cells

• Weight of intestinal mucosa per kg of body weight increases 146%

• Fetus swallows up to 750 mL/d


6/1/15 31

Colostrum is the transition from intrauterine to extrauterine nutrition in mammals

• In composition and bioactivity, colostrum is more like amniotic fluid than it is like mature milk:

• ≥ 13 identified growth factors target GIT • Growth factors function synergistically, in that the combined effect is greater than that of individual factors • Epidermal Growth Factor (EGF) is > 1000 times higher in colostrum than maternal serum • EGF is absorbed intact from the GIT, and may affect growth of distal organs • EGF receptors in infant GIT and lungs • 68 cytokines in human colostrum, changing over first few days after delivery

Kidwell & Salomon, in Atkinson & Lonnerdal, 1996; Kverka et al., Clinical Chemistry 53: 955-962; Sangild. Exp Biol Med 231: 1695-1711, 2006; Jensen et al.. J Nutr 131: 3259-3265, 2001.; Mei et al. Livestock Science 105: 214-222; 2006; Ustundag et al, Mediators of Inflammation, 2005. Wagner, et

al., Clinic Rev Allerg Immunol 34:191-204, 2008.

Distinct Gene Expression at Different Stages of Lactation

Lemay DG, Ballard OA, Hughes MA, Morrow AL, et al. (2013) RNA Sequencing of the Human Milk Fat Layer Transcriptome Reveals Distinct Gene Expression Profiles at Three Stages of Lactation. PLoS ONE 8(7): e67531. doi:10.1371/journal.pone.0067531

http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067531

• Colostrum • Transitional Milk • Mature Milk

• Explains importance of colostrum

• Differentiates colostrum from mature milk

• Explains gradual closing of tight junctions in mammary epithelium

• Emphasizes never to discard colostrum

• Illustrates correct storing and labeling of colostrum

From Evidence to Practice From Evidence to Practice

• Special 11 mL container for colostrum

• Families number pumpings from 1-60

• Bedside nurse quickly identifies the order in which colostrum should be fed to the infant

• Colostrum is fed from first feed through 130 to 150 mL/kg/d

Rodriguez, Meier, Greer, Zeller, 2009; Rodriguez et al, 2010; Rodriguez et al, 2011; Seigel et al., 2013; Lee et al, 2015

Oropharyngeal Administration of Colostrum

• Cytokines in colostrum may be absorbed via the OFALT system and provide systemic protection

• Oligosaccharides may interfere with adherence of pathogens to mucous membranes in the oral cavity and oropharynx and protect from VAP

• BOTH mechanisms would be additive to intestinal effects of colostrum

Several lines of evidence suggest that health and neurodevelopmental outcomes for premature infants have their origins in the immature gut

•  Colonization with commensal bacteria

•  Down-regulation of inflammation and oxidative stress

•  Programming immunomodulatory and metabolic pathways

Keunen et al., 2015; Collado et al., 2012; Al-Asmakh et al., 2012


Several lines of evidence suggest that artificial milks exert a separate, detrimental

effect on the growth, maturation and integrity of the gut epithelium

Clinical Outcomes Experimental Mechanisms

Khodayar-Pardo P, et al. Impact of lactation stage, gestational age and mode of delivery on breast milk microbiota. J Perinatol 2014, 34: 599-605 Perez et al. Bacterial imprinting of the neonatal immune system: Lessons from maternal cells. Pediatr 2007; 119: e724-e732. Martin et al. Human milk is a source of lactic acid bacteria for the infant gut. J Pediatr 2003; 143: 754-8

Cabrero-Rubio et al. The human milk microbiome changes over lactation and is shaped by maternal weight and mode of delivery. AJCN,2012, 96 (3): 544-551. Hunt et al., Characterization of the Diversity and Temporal Stability of Bacterial Communities in Human Milk. PLoS ONE 6: e21313. doi:10.1371/journal.pone.0021313. Jeurink et al. Human milk: a source of more life than we imagine. Beneficial Microbes, 2013: 17-30. Jost et al. Assessment of bacterial diversity in breast milk using culture-dependent and culture-independent approaches. Br J Nutr ; published online 14 Mar, 2013.

American J Respiratory and Critical Care Medicine, 190: 298-308, 2014.

The Rush Research Team

Janet Engstrom, PhD, RN, CNM

Harold Bigger, MD Tricia Johnson,

PhD

Aloka Patel, MD

Beverly Rossman, PhD, RN

Lou Fogg, PhD

Judy Janes, RN, IBCLC

Paula Meier, PhD, RN Kousiki Patra, MD

Rebecca Hoban, MD

Health Outcomes and Cost of Human Milk Feedings for VLBW Infants

• Prospective cohort study • 430 VLBW Infants enrolled Feb, 2008-Jan, 2013 • Variables Included:

• Dose and Exposure Period of HM Feedings • Health Outcomes

• Enteral feed intolerance • Late onset sepsis • Necrotizing enterocolitis • Chronic lung disease • Retinopathy of prematurity • Periventricular leukomalacia • Growth velocity (wt, length, HC)

• Cost of NICU Care • Maternal and Institutional Costs of Providing HM

NIH grant: NRO10009, 2007, Meier, PI

Health Outcomes and Cost of Human Milk Feedings for VLBW Infants*

• 95% of eligible infants were enrolled • 98% received some HM from the mother (3 mLs - 28,229 mLs)

• Days 1-14: •  Median Cumulative HM-PCT = 100% •  76.8% received exclusive HM

• Days 1-28: •  Median Cumulative HM-PCT = 98% •  59.7% received exclusive HM

• NICU hospitalization: •  Average HM-DD = 61 mL/kg/d •  Average HM-PCT = 48.6% NIH grant: NRO10009, 2007,

Meier, PI


Characteristic (N = 430)

Mean ± SD or N (%)

Infant Birthweight (g) 1046 ± 256

Infant Gestational Age (wks) 28.0 ± 2.4

Length of NICU Stay (d) 73.8 ± 41.9

Male Gender 229 (53%)

Maternal Race • Black • Hispanic • Caucasian

• 223 (52%) • 114 (27%) • 83 (19%)

Maternal WIC Eligibility 298 (70%) 6/1/15

• Age: 27.2 ± 6.5 • Education: 13.2 ± 2.8 • Pre-pregnancy BMI: 28.7 ± 7.5 • Black: 30.1 • Hispanic: 27.7 • Caucasian: 26.7 • Cesarean delivery: 65% • Major morbidity: • Hypertension: 31.3% • Diabetes: 8.3% • Mental Health Dx: 17.1%

Tricia Johnson, PhD

Neonatology, 2015

Any Formula (< 100% HM-‐PCT) During Days 1-‐14 Post-‐Birth Increases the Risk of NEC

•  The Risk of NEC was modeled using a propensity score to control for variables that impact NEC (e.g., days NPO, antibiotic use, TPN, etc.)

•  Various HM variables were added to the statistical model AFTER controlling for the risk of NEC. Formula by day of life 14 increases risk of NEC (OR =3.0, p = 0.03)

•  Each additional 1 ml/kg/d of HM during days 1-14 decreases NICU costs by $560.

Marginal effect (in USD) p value

NEC $43,897 <0.001

HM-DD for Days 1-14 -$560 <0.001 Model controls for birth weight, race, gender, and propensity score

6/1/15

•  N = 175 VLBW infants •  Propensity score combined multiple risk factors into a single metric •  Dose-response relationship between HM-DD during Days 1-28 and

the risk of sepsis and its costs •  Each additional 10 mL/kg/d reduced the risk of sepsis by 19%

Aloka Patel, MD

Day of life

≥50 mL/kg/d $122,938

Prop

ortio

n of

Infa

nts

who

Sur

vive

Fre

e of

Sep

sis

HM-DD Days 1-28 and Risk of Late Onset Sepsis

25-49.9 mL/kg/d $132,099

< 25 mL/kg/d $156,249 Patel, et al, J Perinatol, Jan 2013


Exposure Period of NICU Hospitalization: Human Milk Reduces the Incidence of Chronic Lung

Disease (CLD) and the Duration of Hospitalization

•  203 symmetrically-grown AGA VLBW infants CLD and PGF measured at 36 wks PMA (or prior

to NICU DC, if earlier •  Dose of HM grouped into quartiles (% of enteral

feedings = HM during the NICU •  43% reduction in the risk of CLD with each

increasing HM quartile over the NICU hospitalization

Patel et al., podium presentation, ESPGHAN, Jerusalem, June 2014 Aloka Patel, MD

HM-1 N = 51

HM-2 N = 51

HM-3 N = 51

HM-4 N = 50

p

GA (wk) 27 ± 2 27 ± 2 28 ± 2 28 ± 2 .41

BW (g) 1043 ± 238 1034 ± 257 1130 ± 230 1070 ± 218 .17

Male (%) 51% 49% 41% 50% .75

HM Proportion (%)

3% ± 2% 17% ± 8% 71% ± 17% 100% ± 6% <.001

CLD (%) 35% 31% 24% 12% .039

Growth Velocity g/kg/d

14.6 ± 2.0 15.3 ± 6.9 13.6 ± 2.1 13.8 ± 1.8 .11

PGF (%) 29% 37% 39% 54% .08

NICU Stay (d) 81 ± 35 77 ± 38 69 ± 32 64 ± 23 .048

Does High-Dose HM feeding in the NICU translate into long-term health and

neurodevelopmental outcomes?

•  Direct Impact •  Nutrition: LCPUFAs, cholesterol,

IGF-1, glutamine •  Gut-colonizing •  Anti-inflammatory, anti-oxidant •  Oligosaccharides, stem cells •  Immunomodulatory •  Metabolic programming

•  Indirect Impact •  Reduction in NEC, sepsis, CLD

HM-DD Quintiles

1 (n 37) 2 (n 46) 3 (n 50) 4 (n 53) 5 (n 52)

HM-DD (mL/kg/d) Min-Max

0-7 7-27 27-79 80-116 116-156

Cognitive 90 ± 13 94 ± 11 94 ± 13 94 ± 11 98 ± 12

Language 77 ± 16* 81 ± 13 83 ± 17 85 ± 16 87 ± 15*

Motor 88 ± 12 87 ±17 90 ± 14 92 ± 12 93 ± 11

* p<0.05

Neurodevelopmental Outcome at 20 months, CA N = 241

Johnson et al., 2013

• The “upstart” costs of a human milk feeding program in the NICU are thought prohibitive • Mothers do not maintain adequate milk output because of the lack of evidence-based lactation services that are specific to breast pump dependent mothers • Is provision of these services cost-effective?

Cost of Human Milk vs Formula and Donor Human Milk Feeding

Tricia Johnson, PhD


Donor Milk is a “Do no Harm” Option

56

Bioactive and Nutritional Limitations in Donor Human Milk

Component Pasteurization Cellular Abolished

Lactoferrin 57-80% reduction Immunoglobulins (sIgA, IgG)

Up to 48% reduction

Antioxidant Properties Significant reductions Adiponectin 33% reduction Insulin 46% reduction Soluble CD14 88% reduction Oligosaccharides Different profile Amylase 15% reduction Lipase Abolished

Ewaschuk et al., J Appl Physiol. Nutr. Metab., 2011; Ley et al., Pediatr Res, 2011 Ilcol, Hizli, Ozkan. Leptin concentration in breast milk and its relationship to

duration of lactation and hormonal status. Intl Breastfeeding J, 2006.

Leptin concentration decreases dramatically with the duration of lactation

February 2013

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