Innovations in Human Milk: Putting Evidence to Practice Amy B. Hair, MD Assistant Professor of Pediatrics Program Director of Neonatal Nutrition Program Director of NICU Intestinal Rehab Team Section of Neonatology Department of Pediatrics Texas Children’s Hospital abhair@texaschildrens.org

Disclosures I receive research support from: Prolacta Bioscience® for the Human Milk Cream Length of Stay Multicenter Study (Study PI) I receive speaker honoraria from Prolacta Bioscience®

Overview Benefits of human milk for preterm infants Role of donor human milk-derived fortifier for extremely preterm infants Innovations: An exclusive human milk-based diet Studies in progress and future directions Implementation of an exclusive human milk-based diet

AAP Statement 2012 “Breastfeeding and the Use of Human Milk” “All preterm infants should receive human milk.” Human milk should be fortified, with protein, minerals, and vitamins to ensure optimal nutrient intake for infants weighing <1500 grams at birth Pasteurized donor human milk (DHM), appropriately fortified, should be used if mother’s own milk is unavailable or its use is contraindicated Significant short and long-term beneficial effects of feeding preterm infants human milk American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012; 129(3): e827-e841.

Benefits of Human Milk ↓ Respiratory tract infections and otitis media ↓ Sudden infant death syndrome and mortality ↓ GI infections ↓ Risk of celiac disease and IBD ↓ Asthma, atopic dermatitis and eczema ↓ Incidence of NEC Associated with a decrease in obesity and diabetes Beneficial influence on neurodevelopmental outcomes Possible reduction in severity of retinopathy of prematurity American Academy of Pediatrics Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics. 2012; 129(3): e827-e841.

Necrotizing Enterocolitis NEC is a devastating illness that affects 5.4 to 7.4% of VLBW infants/year (Vermont Oxford Network) Despite years of ongoing research, the exact pathophysiology of necrotizing enterocolitis is still not known Multifactorial Mucosal injury leading to an exaggerated immune response, which then results in bacterial translocation, systemic infection, and inflammation

Necrotizing Enterocolitis Problems of the Neonate. (2007). http://web.squ.edu.om/med-Lib/med/net/E-TALC9/html/clients/who/hcfc_images/necrotising%20enterocolitis%201.jpg

Pasteurized Donor Human Milk Human Milk Banking Association of North America Medolac / Mothers Milk Cooperative Prolacta Bioscience Hospital Based Milk Banks

Texas Children’s Hospital Mothers’ Milk Bank Opened in August 2011 www.texaschildrens.org/milk (832) 824-MILK

Exclusive Human Milk-Based Diet The use of an exclusive human milk-based diet in infants ≤ 1250 grams birth weight is associated with a lower rate of necrotizing enterocolitis (NEC)1,2 and decreased parenteral nutrition days2 An exclusive human milk diet is associated with lower mortality and morbidity compared to a cow milk based protein diet3 Study 1- Decreases NEC by 60% and the rate of NEC needing surgical intervention by 90% Study 2- decreases surgical NEC and TPN days parenteral nutrition days 36 (29,77) vs 27 (14,39) p=0.04 NEC surgery 4 (17%) vs. 0 p=0.036 NEC 5 (21%) vs 1 (3%), p=0.08 1Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): 562-567, 2010. 2Cristafalo et al: Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): 1592-1595, 2013.3Abrams et al: Greater mortality and morbidity in extremely preterm infants fed a diet containing cow milk protein products. Breastfeeding Medicine 9 (6): 281-5, 2014.

An Exclusive Human Milk-Based Diet and NEC¹ Medical NEC by 60% Surgical NEC by 90% NNT to prevent 1 case of NEC is 10 NNT to prevent 1 case of surgical NEC is 8 ¹Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): 562-567, 2010.

Exclusive Human Milk-Based Diet Sullivan et al1 showed that there is no difference in growth between infants fed an exclusively human milk-based diet and infants fed human milk plus bovine milk-based products However, concerns remain related to risks of slow growth in these infants 1Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): 562-567, 2010. 2Cristafalo et al. A Randomized Trial of Exclusive Human Milk Versus Preterm Formula Diets in Extremely Premature Infants. J Pediatr 163 (6): 1592-1595, 2013.

Human Milk Feeding Supports Adequate Growth Exclusive Human Milk-Based Diet Early and rapid advancement of fortification1 104 infants, consecutively followed, BW ≤ 1250 g, received diet until 34 weeks PMA Weight gain 24.8 ± 5.4 g/kg/day, length 0.99 ± 0.23 cm/week, HC 0.72 ± 0.14 cm/week Compared to human milk-fed cohorts (Sullivan et al2) Infants had greater growth in weight and length 43% of infants had postnatal growth failure Diet until 34 weeks PMA Fortification advanced to 8 kcal/oz or 140 kcal/kg/day and 4.4 g/kg/d of protein (mature human milk and feeds of 150 ml/kg/day) up to +10 150 kcal/kg/d and 5.25 g/kg/d protein 3 cases of NEC and 1 case of surgical NEC 1Hair et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: 459. 2Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): 562-567, 2010.

Sullivan et al. J Pediatrics. 20102 Hair et al Study1 Human Milk + HMF 60 (n=104) Sullivan et al. J Pediatrics. 20102 p-value + HMF 40 (n=71) + HMF 100 (n=67) Bovine (n=69) Days to full feeds* 18.2 ± 10.6 24.4 ± 12.7 26.5 ± 18.0 25.0 ± 13.5 <0.001 TPN days† 13 (10,19) 20 (11,33) 20 (13,34) 22 (13,34) Feeds initiated (DOL)* 3.3 ± 2.9 5.6 ± 6.6 4.3 ± 3.9 4.7 ± 4.8 0.56 Fortification of feeds (DOL)* 13.0 ± 8.3 14.1 ± 9.0 21.0 ± 14.9 18.4 ± 9.2 Kruskal-Wallis test for means Kaplan-Meier estimation/ method for medians and (25th,75th %tile) No censoring assumed in Baylor data Full feeds *Mean ± SD, †Median (25th, 75th percentile). DOL = day of life; TPN = total parenteral nutrition. 1Hair et al: Human Milk Feeding Supports Adequate Growth in Infants ≤ 1250 grams birth weight. BMC Res Notes 2013; 6: 459. 2Sullivan et al: An exclusively human milk-based diet is associated with a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based products. J Pediatr 156(4): 562-567, 2010.

Caloric Variation of Human Milk Study of 415 sequential samples from 273 unique donors Analyzed for fat, protein, carbohydrate Mean energy content of milk was 19 kcal/oz 25% of the samples were < 17 kcal/oz 65% were < 20 kcal/oz Fat content was the most variable 3.2 g/dL Wojcik KY, Rechtman DJ, Lee ML et al. Macronutrient analysis of a nationwide sample of donor breast milk. J Am Diet Assoc 109:137-140, 2009.

Human Milk Cream We have the ability to measure the caloric density and macronutrients of human milk IR analyzer Requires < 5 mL of milk A novel donor human milk-derived cream supplement is now available Human Milk Cream or Human Milk Fat is derived from the processing of donor human milk Caloric content is 2.5 kcal/mL Prolact-CR

Randomized Trial of Human Milk Cream as a Supplement to Standard Fortification of an Exclusive Human Milk- Based Diet in Infants 750- 1250 g BW

Objective To evaluate whether premature infants who received an exclusive human milk-based diet and a human milk-derived cream supplement (cream) would have weight gain (g/kg/day) at least as good as infants receiving a standard feeding regimen (control)

Infants 750 to 1250 grams BW receiving exclusive human milk-based diet (Standard Feeding Regimen) Analysis of Mother’s Milk or Donor Milk every 24 hrs CONTROL GROUP Analysis of Mother’s Milk or Donor Milk every 24 hrs INTERVENTION GROUP Caloric Content of Milk ≥ 20 kcal/oz Caloric Content of Milk < 20 kcal/oz Data recorded for Nutrition and Growth until 36 weeks PMA Data recorded for Nutrition and Growth until 36 weeks PMA Addition of Cream Supplement to increase caloric content of milk to 20 kcal/oz Data recorded for Nutrition and Growth until 36 weeks PMA

Addition of Cream to Human Milk Caloric Content of Mother’s Own Milk or Donor HM* Kcal/oz Kcal/100 mL Volume of HM Volume of Cream to Add to HM 19-20 64-67.9 98 mL 2 mL 18-18.9 61-63.9 96 mL 4 mL 17-17.9 57-60.9 94 mL 6 mL 16-16.9 54-56.9 93 mL 7 mL

Comparison of Growth Velocities Control group (n=39) Cream group p-value Weight velocity (g/kg/day) 12.4 ± 3.9* 14.0 ± 2.5 0.03 Length velocity (cm/week) 0.83 ± 0.41 1.03 ± 0.33 0.02 Head circumference (cm/week) 0.84 ± 0.22 0.90 ± 0.19 0.21 Weight velocity from time infant regained BW (g/kg/day) 13.7 ± 4.0 15.7 ± 2.5 Two sample t-test *Mean ± SD

Milk Energy Content (kcal/oz) Houston Site San Antonio Site Mother’s Milk 20 ± 5.6 17.6 ± 5.6* Donor Milk 20.6 ± 1.5 19 ± 2.1* *p<0.001 Analyzer overestimated by 1.2 kcal/oz for both groups 21.2/18.8 21.8/20.2 Average of 1.2 kcal/oz higher for unity analyzer than lab methods, confidence interval 0.7-1.7 kcal/oz

Clinical Outcomes Control group (n=39) Cream Necrotizing enterocolitis (%) Sepsis (%) 7.7 10.3 Death (%) p=1.0, Fisher’s exact test

Conclusions Premature infants who received HM- derived cream supplement to an exclusive HM-based diet had superior weight and length velocity compared to infants who did not receive the supplement

Human Milk Cream Follow-up Study Comparing infants who received cream supplement to control group (standard feeding regimen with exclusive human milk-based diet) Currently evaluating as many of the 78 original study infants in follow-up at both study centers 18-24 months corrected gestational age Anthropometrics, Bayley III Neurodevelopmental Exams, triceps skin fold and DXA scans

Effects of Cream Supplement on Length of Stay and Bronchopulmonary Dysplasia The Human Milk Cream Study showed a trend towards a 2-week decreased length of stay for babies who received cream supplement, especially babies who had BPD Randomized Controlled Trial comparing the use of a cream supplement routinely to infants’ exclusive human milk-based diet compared to standard regimen Secondary outcomes include BPD, ROP, mortality, growth, NEC

Necrotizing Enterocolitis and Beyond: Improving Outcomes with Human Milk 1587 infants < 1250 gram birth weight 4 centers in Texas, Florida, Illinois and California

NEC Rates BOV (n=768) HUM (n=819) p-value All NEC % (n) 16.7 (128)   BOV (n=768) HUM (n=819) p-value All NEC % (n) 16.7 (128) 6.9 (53) <0.00001 Medical NEC % (n) 6.1 (47) 2.1 (16) 0.00005 Surgical NEC % (n) 10.6 (81) 4.8 (37) 0.00002

Secondary Outcomes Among All Infants   BOV n=768 HUM n=819 p-value Late onset infection (%) 30.3 19.0 <0.00001 Mortality (%) 17.2 13.6 0.04 Weight gain (g/d) 19.5 ± 8.4 20.3 ± 8.6 0.08 IVH: Grade III or IV (%) 16.8 14.5 0.22 Ventilator days 32.2 ± 44.9 29.3 ± 44.2 0.003 Threshold ROP (%) 9.0 5.2 Patent Ductus Arteriosus (%) 64.7 55.1 0.0001 Bronchopulmonary Dysplasia (%) 56.3 47.7 0.0015 Antenatal steroids (%) 75.2 80.5 0.01 Mean ± SD IVH = intraventricular hemorrhage; NEC = necrotizing enterocolitis; ROP = retinopathy of prematurity

Conclusions The use of an exclusive HM-based diet is associated with significant benefits for extremely premature infants < 1250 gram BW Decreased medical and surgical NEC Decreased late onset sepsis Decreased mortality Decreased bronchopulmonary dysplasia and ventilator days Decreased retinopathy of prematurity

Multicenter Follow-up Study Combine multicenter data of infants at 2 and 5 years of age Exclusive human milk-based diet Bovine milk-based diet Compare outcomes Bayley III scores Growth

Objective: Determine the Effect of Syringe Orientation on Fat Retention Hypothesis: Fat retention will be greatest with the syringe facing “up”, and lowest with syringe “down” Discuss At TCH, syringes are “flat” in NICU. “down” “flat” “up”

Determine the Effect of Syringe Orientation on Fat Retention Fat Content vs. Infusion Time with Varying Syringe Positions Fat Retention (%) with Varying Syringe Positions

“Pump It Up” Make sure syringe tip is positioned “up” when giving feeds to all babies Avoid using extension tubing when feasible You can help our NICU babies grow by making sure they receive all the nutrients they can from syringe feedings

Studies in Progress Use of an all human milk-based diet in infants with single ventricle congenital heart disease Multicenter Study Large Cardiac Centers Dr. Cynthia Blanco and Dr. Jose Perez are lead PIs Comparing an all human milk-based diet to bovine fortifiers Canada and Europe

Studies in Progress Long-term cost analysis of an all human milk- based diet

Future Directions Use of an exclusive human milk-based diet in other high risk infant populations Congenital Heart Disease Fluid restricted infants Abdominal Wall Defects Human Milk Oligosaccharides (HMOs) Lacto-engineering

Implementation Evaluate your highest risk population for NEC and feeding intolerance Gather data regarding NEC rates, TPN days, and feeding intolerance so you have a baseline Implement Donor Human Milk and DHM Fortifier Evaluate your results using balancing measures If cost is an issue consider collecting data including length of stay as a surrogate marker Often budgets for nutrition are limited

Decreased cost and improved feeding tolerance with Exclusive HM diet 293 infants studied 23-34 weeks and BW 490-1700 g Retrospective study with 3 groups: Exclusive HM- mother’s milk + donor milk + donor milk derived fortifier Mother’s milk + bovine fortifier Mother’s milk + bovine fortifier + formula Non-industry funded study Assad et al. Journal of Perinatology 2015

Decreased cost and improved feeding tolerance with Exclusive HM diet Exclusive Human Milk group Less feeding intolerance Less number of days to full feeds Less NEC Similar growth between all groups Total hospitalization costs were lower by up to $106,968 per infant in those fed Exclusive Human milk compared to other groups NEC 10% to 1.1% Assad et al. Journal of Perinatology 2015

Costs- Exclusive HM Diet Costs of NEC and cost-effectiveness of exclusively human milk-based diet compared to bovine based diet in extremely premature infants NEC $74,004 and NEC requiring surgery $198,040 Costs over the hospitalization for a preterm infant 100% human milk diet infants had decreased length of stay= cost savings of $8,167 Using mother’s milk with different fortifier What is the cost of a good outcome? Infants with surgical NEC have increased risk of re-hospitalization and poor neurodevelopment, extra $$, quality of life Ganapathy V, Hay JW, Kim JH. Costs of Necrotizing enterocolitis and cost-effectiveness of exclusively human milk based products in feeding extremely premature infants. Breastfeed Med. 7(1):29-37, 2012.

Implementation Increase maternal milk supply for premature infants Pumps at the bedside Education about benefits of mother’s own milk Lactation Support Use of Pasteurized Donor Human Milk Milk Bank Availability Drop off site for donated human milk Potential variability in energy density of donor human milk depending on milk bank

Implementation Standardized Feeding Protocol

Feeding Guidelines ≤ 1250 g BW Day of Feed Human Milk [EBM or Donor] kcal/oz Feeding Volume (mL/kg/d) TPN Lipids Total Fluids = Enteral + TPN + IL (mL/kg/d) 1 20 15-20 90-100 5-10 120 2 95-105 10-15 130 3 115-120 15 150 4 40 95 5 24 (add donor milk-derived fortifier +4) 60 75 EBM = expressed breast milk; IL = intravenous lipid; TPN = total parenteral nutrition. Baylor College of Medicine, Section of Neonatology, Department of Pediatrics. Guidelines for Acute Care of the Neonate. 23rd Ed. 2015-2016.

Feeding Guidelines ≤ 1250 g BW Day of Feed Human Milk [EBM or Donor] kcal/oz Feeding Volume (mL/kg/d) TPN Lipids Total Fluids = Enteral + TPN + IL (mL/kg/d) 6 24 (donor milk-derived fortifier +4) 80 55-70 15 or Off Lipids 150 7 26 (add donor milk- derived fortifier +6) 100 50 8 26 (donor milk-derived fortifier +6) 120 Off TPN 120 Off TPN or IV fluids 9 140 10 28 (donor milk-derived fortifier +6)+ cream (2 kcal/oz) 160 160 Full enteral feeds Baylor College of Medicine, Section of Neonatology, Department of Pediatrics. Guidelines for Acute Care of the Neonate. 23rd Ed. 2015-2016.

Positive Outcomes to Follow Rates of Necrotizing Enterocolitis Central line days, Parenteral Nutrition Days CLABSI infection Growth- weight, length, head circumference Postnatal growth failure Feeding tolerance- number of times feeds are stopped and restarted Costs $$, Decreased Length of Stay Number of infants not transferred to higher level of care

Implementation Extra Costs Implementation Administrative Staffing Milk Bank Techs, Nurses, Preparing Milk Donor Milk and DHM Fortifier Storage (Freezer) Implementation Education of Staff Implement Consent / Assent of Parents Risk of Milk Errors Possible Delay of Enteral Feeding Awaiting Mother’s own milk or Donor Human Milk Consent

We Should Strive for the Best Possible Long Term Outcomes Liam- 26 weeks, 800 grams

Questions?