Nutrition for the Preterm Infant: Developing a Plan

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1 Disclosure Nutrition for the Preterm Infant: Developing a Plan Penni Davila Hicks, PhD, RD Medical Science Liaison Abbott Nutrition Columbus, Ohio I am currently an employee of Abbott Nutrition Images and Photographs used in this presentation are from copyright approved sources I will make no recommendation for an offlabel use of any product in this presentation Objective Review the data related the importance of nutrition during the NICU care Review the evidence for when and what to enterally feed the VLBW infant Discuss the evidence on the establishment of feeding protocols Be able to assess efficacy of nutrition intervention What is the Nutritional Gold Standard for Preterm Infants? To approximate the rate of growth and composition of weight gain for a normal fetus of the same postconceptional age To maintain normal concentrations of nutrients in blood and tissue AAP/CON: Nutritional needs of the preterm infant. In Kleinman RE (ed). Pediatric Nutrition Handbook, 6th ed. Academy of Pediatrics, 2009, pp 79. 1

2 The third trimester of pregnancy A critical period for babies Critical time for brain development - Cerebral cortex enlarges There is a rapid increase in the amount of body fat: Fat layer develops for temperature regulation High placental transfer of important nutrients (e.g., protein, calcium, phosphorus, zinc, etc. - most of this during the third trimester). 31 wks GA 40 wks GA First Year of Life Represents a Critical Opportunity for Brain Growth First year of life provides an important opportunity for the growth of the baby s body and brain to compensate for earlier deprivation First Year of Life Represents a Critical Opportunity for Brain Growth Nutrition and Catch-Up Growth NICHD Growth Observational Study In VLBW infants, failure to catch up in weight by 8 months was associated with Lower Bayley development quotients Smaller head circumferences Higher rate of neurosensory impairment x x Extrauterine Growth Restriction x N = 1660 *P< Hack M, et al. Am J Obstet Gyn. 1982;143: Ehrenkranz RA, et al. Longitudinal growth of hospitalized very low birth weight infants. Pediatrics. 1999;104;

3 Evidence of Postnatal Growth Failure Poor Weight Gain Associated with Morbidity ELBW infants who experienced the slowest rate of inhospital weight gain had the highest morbidity Weight gain,12.0 vs 21.2 g/kg/day NEC 20% vs 4% Late-onset sepsis 83% vs 55% BPD 56% vs 31% Postnatal steroid therapy 64% vs 30% Poindexter B. In Koletzko B, Poindexter B, Uauy R, eds. Nutrition Care of the Premature Infant. Basal Switzerland:: Karger 2014;110: Ehrenkranz RA, et al. Pediatrics 2006;117: Poor Weight Gain Increases Odds for Poor Outcomes ELBW infants, in-hospital growth: 12.0 vs 21.2 g/kg/day Poor Head Circumference Increases Odds for Poor Outcomes ELBW infants, in-hospital HC growth: 0.67 vs 1.17 cm/wk Cerebral palsy Cerebral palsy 8.00 ( ) 4.10 ( ) Bayley MDI <70 Bayley MDI < ( ) 2.33 ( ) Neurodevelopmental Impairment 2.53 ( ) Neurodevelopmental Impairment 3.64 ( ) MDI=Mental Development Index Odds Ratio (95% Confidence Interval) HC=Head circumference MDI=Mental Development Index Odds Ratio (95% Confidence Interval) Ehrenkranz RA, et al. Pediatrics 2006;117: Ehrenkranz RA, et al. Pediatrics 2006;117:

4 Goals for Growth in the NICU From return to birth weight through discharge Weight gain >18g/kg/d HC >0.9 cm/wk are associated with better neurodevelopmental and growth outcomes If rates falter, the infant s nutrition should be reviewed and, if possible, modified to achieve target growth parameters Focus on protein content and protein/energy ratio of feeds Recognize that the intake prescribed is not always administered Utilize nutrient-enriched feeding strategies to help reduce the magnitude of cumulative nutritional deficits Preterm Infants at Hospital Discharge May Exhibit the Following An accumulated energy deficit An accumulated energy deficit Inadequate bone mineralization Low body stores of nutrients Ehrenkranz RA, et al. Pediatrics 2006;117: Energy: Weekly Intake and Cumulative Deficit Protein: Weekly Intake and Cumulative Deficit * 30 weeks 31 weeks * P <.001 * 30 weeks 31 weeks * P <.001 * * Birth Weeks Embleton NE, et al. Pediatrics. 2001;107: Birth Weeks Embleton NE, et al. Pediatrics. 2001;107:

5 Infant Nutrition Trophic Feedings-Meta-analysis Is Early BETTER Than Late? Trophic feedings defined Milk volumes up to 24 ml/kg/d introduced before 96 hours postnatal age and continued until at least one week after birth Nine trials of 754 VLBW infants ( ) No evidence that early trophic feeding affected feed tolerance or growth rates in VLBW infants Meta-analysis did not detect a statistically significant effect on the incidence of NEC (typical relative risk 1.07 Bombell S, McGuire W. Early trophic feeding for very low birth weight infants. Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD DOI: / CD pub3. Delayed Enteral Feedings-Meta-analysis Enteral feeds for VLBW infants are often delayed for several days or longer after birth due to concern Feed may not be tolerated or may increase the risk of NEC Five RCTs with a total of 600 infants Defined delayed introduction as later than five to seven days after birth and early introduction as less than four days after birth Two trials, total of 488 infants, only recruited growthrestricted infants Delayed Enteral Feedings-Meta-analysis Meta-analyses did not detect statistically significant effects on the risk of NEC (relative risk 0.89), or all cause mortality (relative risk 0.93) Infants who had delayed introduction of enteral feeds took significantly longer to establish full enteral feeding (reported median difference three days) Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD DOI: / CD pub3. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD DOI: / CD pub3. 5

6 Continuous vs. Intermittent Tubefeeding- Meta-analysis Seven trials, involving 511 infants No differences in time to achieve full enteral feeds between feeding methods No significant difference in somatic growth and incidence of NEC between feeding methods irrespective of tube placement. Continuous vs. Intermittent Tubefeeding- Meta-analysis Small sample sizes, methodological limitations, inconsistencies in controlling variables that may affect outcomes, and conflicting results of the studies to date make it difficult to make universal recommendations regarding the best tube feeding method for premature infants less than 1500 grams. Premji SS, Chessell L. Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD DOI: / CD pub2. Premji SS, Chessell L. Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams. Cochrane Database of Systematic Reviews 2011, Issue 11. Art. No.: CD DOI: / CD pub2. Slow Advancement of Feeding to Prevent NEC-Meta-analysis Four randomized controlled trials with a total of 496 infants Slow advancement-daily increments of 15 to 20 ml/kg and faster advancement-30 to 35 ml/kg Slow Advancement of Feeding to Prevent NEC-Meta-analysis No statistically significant effects on the risk of NEC (relative risk, 0.91), or all cause mortality (relative risk,1.43,) Infants on slow advancement took significantly longer to Regain birth weight (median difference 2 to 6 days) To establish full enteral feeding (median difference 2 to 5 days) Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD DOI: / CD pub3. Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants. Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD DOI: / CD pub3. 6

7 Formula vs. Donor Human Milk Eight trials with a total of 1017 infants <32 wks GA and BW <1800 g Most studies were from the late 1970 s and early 1980 s, except for one from 2005 which was the only one to use nutrient-fortified donor milk Data from 5 trials demonstrated a significantly higher incidence of NEC in the formula fed group ( relative risk 2.5 ) Formula vs. Term Human Milk Six trials, all initiated more than 20 years ago, fulfilled the pre-specified inclusion criteria. No trials comparing feeding with formula milk versus nutrient-fortified term human milk were found. In preterm and LBW infants, feeding with formula compared with unfortified term human milk resulted in a greater rate of growth in the short term. No statistically significant difference in the incidence of necrotizing enterocolitis, The single trial that evaluated longer-term outcomes did not find evidence of an effect on longer-term growth and neurodevelopment. Quigley M, Henderson G, Anthony MY, McGuire W. Formula milk versus donor breast milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No.: CD DOI: / CD pub2. Henderson G, Anthony MY, McGuire W. Formula milk versus term human milk for feeding preterm or low birth weight infants. Cochrane Database of Systematic Reviews 2001, Issue 4. Art. No.: CD DOI: / CD Donor Term vs. Donor Preterm Human Milk Infant Nutrition No studies met the inclusion criteria. Nutrition NOT Feeding Dempsey E, Miletinj. Banked preterm versus banked term human milk to promote growth and development in very low birth weight infants. Cochrane Database Syst Rev Jun 16;(6):CD

8 Comparison of Daily Intake of 120 kcal/kg Comparison of Daily Intake of 120 kcal/kg Feeding ml/kg* Protein g/kg Calcium mg/kg Phosphorus mg/kg Feeding ml/kg* Protein g/kg Calcium mg/kg Phosphorus mg/kg Preterm human milk Term human milk Fortified Preterm Human Milk Preterm formula Term infant formula LSRO, (< 2.5 kg) LSRO, (< 2.5 kg) AAP-CON, 2008 (< 1 kg) AAP-CON, 2008 (1-1.5 kg) * Volume needed to provide a daily intake of 120 kcal/kg * Volume needed to provide a daily intake of 120 kcal/kg Enteral Protein Intake Associated With Improved Weight Gain Ernst KD, et al. J Perinatol 2003;23: Wt gain 6.5 g/d each additional g of protein N=69 infants <1000 g. R 2 = Average Protein Intake (g/kg/d) Recommended Enteral Protein Intakes for VLBW Infants Recommendation 1. Ziegler E. J Pediatr Gastroenterol Nutr 2007;45:S170-4; 2. Klein CJ. J Nutr 2002;132:1395S-1577S; 3. Kleinman RE (ed): Pediatric Nutrition Handbook.Elk Grove Village, IL, American Academy of Pediatrics, Canadian Paediatric Society, Nutrition Committee. Can Med Assoc J 1995;152: ; 5. Agostoni S et al. J Pediatr Gastroenterol Nutr 2010;50:1-9. g/kg/day Ziegler et al, Life Science Research Office, AAP Committee on Nutrition, Canadian Paediatric Society, Birth weight <1 kg Birth weight 1 kg ESPGHAN Recommendations 5 Birth weight <1 kg Birth weight kg

9 Comparison of Protein Requirements and Enteral Options Recommendation g/kg/day Ziegler et al, Life Science Research Office, AAP Committee on Nutrition, ESPGHAN, / Enteral Options: Unfortified preterm breast milk 2.4 Fortified preterm breast milk Fortified term breast milk Preterm formula Preterm formula 24 high protein Ziegler E. J Pediatr Gastroenterol Nutr 2007;45:S170-4; 2. Klein CJ. J Nutr 2002;132:1395S-1577S; Kleinman RE Pediatric Nutrition Handbook.Elk Grove Village, IL, American Academy of Pediatrics, Agostoni S et al. J Pediatr Gastroenterol Nutr 2010;50:1-9. g/kg/d when fed at 120 kcal/kg/d Early Studies of Very High Protein Intake Goldman HI, et al. J Pediatr 1969;74:881-9; Goldman HI, et al. J Pediatr 1971;78: Modified term infant formula Protein levels: 20 g/l vs 40 g/l Current term formulas have 15 g/l Infants received protein at either g/kg/d or g/kg/d Infants on higher protein formula had more fever, lethargy, and poor nipple feeding; higher plasma protein levels; less edema Follow-up at 3 years of age higher protein intake associated with Increased risk of strabismus Lower IQ scores in children who were SGA or BW <1300 g Infant Nutrition Growth NOT Weight Growth Rates With Varying Enteral Protein and Energy Intakes Formula Protein, g/kg/d Energy, kcal/kg/d Protein/Energy, g/100 kcal Group 1 n= Group 2 n= Group 3 n= Outcomes Δ Weight, g/kg/d 16.0 (1.8)* 19.1 (3.2) 21.5 (2.2) Δ Length, cm/wk 1.04 (0.18) 1.21 (0.34) 1.28 (0.47) Δ HC, cm/wk 0.98 (0.11) 1.15 (0.25) 1.24 (0.26) Δ Skinfold thickness, mm/wk (0.21) 0.77 (0.28) 1.22 (0.31)* *Significantly different from other 2 groups; triceps and subscapular skinfolds. Kashyap S, et al. J Pediatr 1988;113:

10 Formulas/Fortifier Designed for Preterm Infants Is there history of use in the intended population, high-risk preterm infants? Do babies grow well on the formula/fortifier? Are they well tolerated? Are they backed by science? Goals of Human Milk Fortification Enrich human milk to match higher nutritional requirements of premature infants to improve growth and nutrient status Preserve unique benefits of human milk Avoid interference with absorption of milk nutrients Avoid adverse events related to fortifier Maintain anti-infective/immunologic benefits of human milk Study Design Human Milk Fortifier Clinical Study-Growth N=144 BW <1600 g Gest <33 wks Control HMF (n=70) Study Day 1 (SD 1) SD 15 SD 29 Study HMF 1 n=37 Control HMF 1 n=30 Targeted Growth 2 Birth Full Strength Fortification Or to discharge Weight gain, g/kg/d Length gain, cm/wk 18.4 ± 3.0* 14.3 ± ± ± 0.33 > 18 NA Randomized Prior 21 days old Study HMF (n=74) 100 ml/kg/d HC gain, cm/wk 1.06 ± ± 0.22 > 0.9 * p= p= p= Data Collection Barrett-Reis B, Pediatrics, Barrett-Reis et al, Pediatrics Ehrenkranz RA et al, Pediatrics

11 Lean body Mass, kg % Fat Absorption Fat Mass, kg 10/22/2015 Fat Absorption with Different Ca Salts * P = Soluble Insoluble Schanler, R, Henderson TR, Hamosh M. Fatty acid soaps may be responsible for poor fat absorption in premature infant fed fortified human milk. J Pediatr, * Rochow et al Study Part 1 Infants < 34 weeks GA Human milk fed Stratified by BW (<1000 g, g, >1500 g N=15 per group A priori, interim analysis when half of infants enrolled Stop study if metabolic acidosis > 60% Incidence of metabolic acidosis in infant fed HM and SF over past 2 yrs was determined (historical control) matched for gender, GA, BW Rochow N, Jochum F, et al. Fortification of breast milk in VLBW infants: Metabolic acidosis is linked to the composition of fortifiers and alters weight gain and bone mineralization. Clinical Nutrition 2011;30: Body Composition Infant Nutrition 8 ARA + DHA [FF] ARA + DHA [ETG] Control * 8 Early is BETTER Than Late * Late is BETTER Than Never Growth NOT Weight * P < Age, months post-term Age, months post-term Nutrition NOT Feeding Groh-Wargo,

12 Infant Nutrition Nutrition plan for preterm infants Develop a plan Birth Discharge Transition phase In-Hospital growth phase Postdischarge phase Test the plan Implement the plan Weight Nutrition goal: match intrauterine growth rates Nutrition goal: provide for Catch Up growth Days Stick to the plan Canadian Pediatric Society. CAN MED ASSOC J 1er JUIN 1995; 152 What to Focus on Who Should be Involved Initiation of parenteral nutrition Initiation of enteral nutrition Advancing enteral nutrition Desired human milk feedings Fortification of breast milk Oral feeding Assessment of growth Discharge feedings Neonatologist(s) with interest in nutrition NICU dietitian Clinical pharmacist Nurse practitioners Nurse with dedication to nutrition Lactation consultant(s) Others 12

13 Next Steps in Feeding Protocol Development Literature review Prepare a proposal Engage practitioners and neonatologists Consensus of healthcare team Education of healthcare professionals Trial protocol Implementation of approved protocol nurserywide and ongoing education and assessment Patole and de Klerk, 2005 Meta-analysis To systematically review the observational studies reporting incidence of NEC in preterm, LBW neonates before and after implementation of a standardized feeding protocol Preterm and low-birth-weight infants Patole SK, de Klerk. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child 2005;90:F147-F151. Patole and de Klerk, 2005 Six eligible studies ( ) were identified. A significant heterogeneity was noted between the studies indicating the variations in the population characteristics and feeding practices over a period of 25 years. Meta-analysis of the six studies revealed a pooled risk ratio of 0.13 (95% confidence interval 0.03 to 0.50) that is, introduction of a standardized feeding regimen reduced the incidence of NEC by 87%. Conclusion: Standardized feeding regimens may provide the single most important global tool to prevent/minimize NEC in preterm neonates. Randomized controlled trials are needed. Smith et al., 2005 Prospective observational study design To assess if the stated goals in the standardized feeding protocol for VLBW infants could be met as the protocol was being implemented BW grams, GA weeks Sample size-49 infants Patole SK, de Klerk. Impact of standardised feeding regimens on incidence of neonatal necrotising enterocolitis: a systematic review and meta-analysis of observational studies. Arch Dis Child 2005;90:F147-F151. Smith JR. Early Enteral Feeding for the Very Low Birth Weight Infant: The Development and Impact of a Research-Based Guideline. Neonatal Network. 2005;24(4):

14 Results Goal of initiating feeds on day of life 2 was met 60% of the time 73% received breast milk as the first feeding 78% achieved full feeds within the first week of life NEC rate decreased from 1.5% to <0.6% Goals of the guidelines were met Use of a lactation consultant and an RD were emphasized Donovan et al., 2006 Retrospective study design To determine if implementation of a feeding protocol can improve: Time to return to birth weight Time to reach full enteral feeds Average daily weight gain BW <1250 grams Sample size-23 infants in the pre-implementation group, 70 infants in the post-implementation group Smith JR. Early Enteral Feeding for the Very Low Birth Weight Infant: The Development and Impact of a Research-Based Guideline. Neonatal Network. 2005;24(4):9-19 Donovan R, Puppala B, Angst D, Coyle BW. Outcomes of Early Nutrition Support in Extremely- Low-Birth-Weight Infants. Nutr in Clin Prac. 2006;21: Results Time to initiate enteral nutrition decreased from hr of life to hr of life (p<0.01) Reduction in time to return to birth weight in the postimplementation group (NSD, p=0.06) The post-implementation group reached full enteral feedings significantly sooner than the pre-implementation group (DOL pre vs post; p<0.01) Two infants in each group developed NEC during the course of the hospital stay Street et al., 2006 Prospective observational study design To determine if implementation of a standardized feeding protocol was associated with less variability in certain feeding related outcome Length of time to first enteral feeding Number of days NPO Time to achieve 80 ml/kg/day of enteral nutrition BW <2000 grams Sample size-58 in pre-implementation group, 68 infants in post-implementation group Donovan R, Puppala B, Angst D, Coyle BW. Outcomes of Early Nutrition Support in Extremely- Low-Birth-Weight Infants. Nutr in Clin Prac. 2006;21: Street JL, Montgomery D, Adler SC, Lambert DK, Gerstmann DR, Christensen RD. Implementing Feeding Guidelines for NICU Patients <2000 g Results in Less Variability in Nutrition Outcomes. J Parent Ent Nutr. 2006;30(6):

15 Results The length of time to initiate the first feed was not significantly different between the two groups but there was significantly less variability in initiating enteral nutrition (0-24 d pre vs. 0-6 d post; p<0.01) Range of NPO days was less in the postimplementation group (0-23 d pre vs d post; p<0.001) Significantly less variability in the length of time to achieve 80 ml/kg/day in the post-implementation group (2-53 pre vs post; p<0.01) No difference in NEC between the two groups Street JL, Montgomery D, Adler SC, Lambert DK, Gerstmann DR, Christensen RD. Implementing Feeding Guidelines for NICU Patients <2000 g Results in Less Variability in Nutrition Outcomes. J Parent Ent Nutr. 2006;30(6): McCallie et al., 2011 Retrospective study design To evaluate the impact of a standardized feeding protocol on: Time to full feeds TPN days NEC rates and rates of late onset sepsis Number of infants discharged below the 10 th percentile who were AGA at birth BW <1500 grams Sample size-96 infants before feeding protocol was instituted and 93 after McCallie KR, Lee HC, Mayer O, Cohen RS, Hintz SR, Rhine WD. Improved Outcomes with a Standardized Feeding Protocol for Very Low Birth Weight Infants. J Perinatol. 2011;31:S61-S67 Results ELBW infants in the post-implementation group reached 120 and 160 ml per kg per day faster (120mL meal DOL 43.9 vs. 32.8; p = ml/kg mean DOL 48.5 vs. 35.8; p = 0.02) Fewer days on TPN (46.2 vs 31.3; p = 0.01) No difference in days to regain birth weight (p=0.63) NEC and late onset sepsis significantly decreased in the post-implementation group (18% vs. 3%; p = 0.01) Severe growth restriction (<3 rd percentile) was reduced in Post-implementation group after 28 days (36% vs. 11%; p=0.002) 36 weeks gestational age (39% vs. 20%; p=0.03) At hospital discharge (35% vs. 17%; p=0.03) McCallie KR, Lee HC, Mayer O, Cohen RS, Hintz SR, Rhine WD. Improved Outcomes with a Standardized Feeding Protocol for Very Low Birth Weight Infants. J Perinatol. 2011;31:S61-S67 Hansen et al., 2011 Retrospective study design To determine if implementation of a standardized feeding protocol can: Improve consistency of nutrition practices Decrease EUGR at 36 weeks gestational age and at discharge BW <1500 grams Sample size 49 infants in the pre-implementation group, 32 infants in the post-implementation group Hanson C, Sundermeier J, Dugick L, Lyden E, Anderson-Berry AL. Implementation, Process, and Outcomes of Nutrition Best Practices for Infants <1500 g. Nutr Clin Pract. 2011;26(5):

16 Results There was a significant decrease in EUGR at discharge between the two groups (28% pre vs. 9% post; p<0.01) Median weight percentile increased in the postimplementation group (8 th percentile pre vs. 15 th percentile post; p=0.005) Median day of life to initiate enteral nutrition was significantly reduced (9 pre vs. 4 post; p=0.005) Median DOL to full feeds, 150 ml kg -1 d -1, was reduced (DOL 30 vs. DOL 22; p=0.02 NEC remained stable (6% pre vs 3% post) Infant Nutrition Early is BETTER Than Late Late is BETTER Than Never Growth NOT Weight Nutrition NOT Feeding Hanson C, Sundermeier J, Dugick L, Lyden E, Anderson-Berry AL. Implementation, Process, and Outcomes of Nutrition Best Practices for Infants <1500 g. Nutr Clin Pract. 2011;26(5): Focus on Growth Summary Nutrition for the preterm infant is clearly important. Without appropriate nutrients, organ systems will not grow properly and the infant s development will suffer. The evidence on how to feed the high-risk, preterm infant is evolving. Meta-analyses help in making decisions on when and how to feed. 16

17 Summary The preferred feeding for infants is human milk. For preterm infants human milk must be fortified to provide adequate nutrients to the infant. Infant formulas designed for preterm infants are available when human milk is not. Knowledge of the science behind the various feeding modalities is required as evidence-based medicine practices are employed. The establishment of feeding protocols appears to standardize feeding practices and reduces the variability in the feeding process. Ultimately, the outcome of growth must be proactively monitored and timely adjustments made in the nutrition support of the infant. Thank you 17