Human milk fortification

INAC 2017 Human milk fortification Pr Jean-Charles Picaud Neonatology, Hôpital de la croix Rousse Claude Bernard university Lyon 1 Lyon, France

Human milk has specific beneficial effects in preterm infants Sufficient- and good quality- postnatal growth is beneficial for preterm infants Unfortified HM does not support sufficient nutrients intake and postnatal growth ESPGHAN 2010: advocates the use of human milk for preterm infants as standard practice, provided it is fortified with added nutrients where necessary to meet requirements. Fortifed HM is the reference nutrition for VLBW infants during hospitalization

Fortification of HM Objectives: To add precise amounts of fortifier without bacteriological contamination (hygiene) Standard fortification Multicomponent fortifier Individualized fortification Multicomponent fortifier ± Protein, Fat, Carbohydrates Milk preparation center Dedicated room in or close to the unit At bedside Proximity babies + ++ +++ Hygiene +++ ++ + Precision +++ +++ +

Standardized fortification Composition of multicomponent fortifiers and protein fortifier (per g powder) Name Suppletine Fortipré Fortema FM85 Enfa mil Simi lac Nutriprem (Aptamil PS) Manufacturer Lactalis Nestle Danone Nestle MJ Ross Danone Energy (Kcal) 3,6 3,5 3,5 3.6 4.9 (L) 3.9 (L) 3.4 Protein (g) 0,2 0.2 PH 0,3 PH 0.2 EH 0.4 0.3 0.8 PH Na (mg) 6,6 5.2 8,0 5.4 5.6 4.2 7.8 K (mg) 3,0 13.2 5,3 2.3 10.2 17.5 12.3 Ca (mg) 10 15 15 10 32 33 5.2 Ph (mg) 6 9 9 7 18 19 5.2 Iron (mg) 0 0.3 0 0 0.5 0.1 0

Standardized fortification May be inappropriate for some preterm infants fed HM: Slower growth than infants fed a preterm formula Significant proportion are growth retardated at discharge Henriksen 2009: 127 VLBW infants fed fortified (std) HM BW < P10: 33% at birth 58% at discharge Due to Variability of nutrients needs in various clinical situations (ELBW, severe intrauterine growth restriction, BPD, ) NB: ESPGHAN 2010 «No specific recommendations are provided for infants with a weight below 1000 g because data are lacking «The needs of infants with specific diseases (e.g., bronchopulmonary dysplasia, congenital heart disease, short bowel syndrome) are not specifically addressed in this commentary. Variability of nutrients content of human milk

Standardized fortification Multicomponent fortifiers increase osmolality of HM Human milk 290-300 mosmol/kg No evidence was found for a causal relation between the osmolality of nutrients and the development of necrotizing enterocolitis. Delay in gastric emptying if osmolality > 450 mosmol/kg Warning about feeding oral high osmolar electrolyte supplements and medications (Pearson 2012, Kriessl 2013)

mosm/kg Prot. Int. (g/kg.d) Standard fortification of HM: 3 multicomponent fortifiers Protein intake (for 160 ml/kg/d) & osmolality (mosm/kg) * 500 Increased risk > 450 mosm/kg 400 300 5 4 3 2 LM LM + 4% MCF1 LM + 5% MCF2 LM + 4% MCF3 LM + 8% MCF1 1 MCF, multicomponent fortifier 1 (Suppletine), 2 (Fortipre), 3 (Aptamil) * Mean osmolality (3 differents HM) at H24 Osmolality of new products!

Rosas Acta Pediatr 2016 Fresh HM Fortified with extensively hydrolyzed MCF (FM85) Protein supplement D C B A Osmomolality up to 550 mosm/kg

Osmolality (mosm/kg) What happens in the first 2 hours after fortification? 500 suppl4% 450 400 350 2/3 of the increase occurs immediatley at time of fortification 300 250 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 0 1 10 20 30 40 50 60 90 105 120 1440 Time (min) Fortification «at bedside» is not efficient to prevent the significant increase in osmolality Improve multicomponent fortifiers composition

Standardized fortification may help, but could be insufficient to cover the needs of preterm infants Improve standard fortification Individualized fortification Early beginning, Lipids as energy source, Protein content Standardize HM composition Targeted Fortification Evaluate individual protein utilization Adjustable Fortification Optimization of postnatal growth

Standardized fortification may help, but could be insufficient to cover the needs of preterm infants Improve standard fortification Individualized fortification Early beginning, Lipids as energy source, Protein content,. Standardize HM composition Targeted Fortification Evaluate individual protein utilization Adjustable Fortification Optimization of postnatal growth

Standardized fortification Early beginning of multicomponent fortification Early versus Delayed Human Milk Fortification in Very Low Birth Weight Infants A Randomized Controlled Trial (Shah 2016) 100 VLBW infants, multicomponent fortifier started at 20 or 100 ml/kg.d Early Delayed BW (g) 990 990 GA (wks) 27.5 28 SGA (<P10) (%) 26 12 Start to feed (d) 3 3 Age full feed (d) 20 20 Feeding intolerance (%) 31 30 Cumulative protein intake M1 (g/kg) 99 90 SGA at discharge (<P10) (%) 72 68 No significant difference Higher protein intake (energy idem) but no significant effect on feeding tolerance or time to reach full feeding volume. NB: 2/3 infants presented EUGR!

Standardized fortification Improvment of fortifiers composition Human milk based fortifier Not yet fully available in Europe (except in Austria) Cost-benefit ratio in all health care systems? HM consuming Efficacy reported only in NICUs with high prevalence of NEC (16%) (Sullivan et al. 2010)

Standardized fortification Improvment of fortifiers composition Lipids to replace partly carbohydrates as energy source Multicenter randomized controled trial: DIAMOND study Control HM fortifier (chmf=fm85) vs. New HM fortifier (nhmf): Main outcome: weight gain over a 21 days-period Secondary outcomes: digestive tolerance, LC-PUFA status

Composition of fortifiers

Nutrients intake and osmolality 3 g/100 kcal 3.5 g/100 kcal * Calculation based on the composition of preterm HM: 1.6 g & 67 kcl per 100mL Osmolality at H24 475 425 (mosm/kg)

EFFICACY : Weight gain

EFFICACY : LC-PUFAs Agostoni 2010 Recommendations 350-400 >55 5-15:1 18-42 12-30 1-2:1 <30%DHA DHA at D21 chmf nhmf P Red blood cell 5.1 ± 0.9 5.6 ± 1.2 0.016 phosphatidylethanolamine

TOLERANCE Digestive tolerance No difference Metabolic tolerance: Serum urea

In summary, the new fortifier Increased protein content (en protein to energy ratio) helped to improved short-term weight gain Replacement of carbohydrates by lipids reduction of osmolality good digestive tolerance Improvment of LC-PUFAs status

Standardized fortification may help, but could be insufficient to cover the needs of preterm infants Improve standard fortification Individualized fortification Lipids as energy source, protein content, early beginning Standardize HM composition Targeted Fortification Evaluate individual protein utilization Adjustable Fortification Optimization of postnatal growth

Individualized fortification of HM Targeted Fortification Analysis of HM and then fortification to reach the targeted nutrient intake (NB: requires frequent milk analyse) by adding: - protein: Polberger 1999 - lipids: De Halleux 2007 - prot, fat, carbohydrates: Rochow 2013, McLeod 2016 RCT Marlocchi 2016 Makes an assumption about nutrient s needs (ESPGHAN 2010: HM! ELBW!) Adjustable fortification Protein fortification adjusted to the metabolic response evaluated through periodic determinations of serum urea - Arsanoglu 2010 RCT - Alan 2015 Takes into consideration actual protein status in each infant

Individualized targeted fortification of HM Rochow 2013: single center, prospective case-control study HM + HMF (Similac) Only ±Fat±Prot±Carbohydr. (n=10) (n=20) BW (g) 880±240 860±310 GA (wks) 27.1±1.6 26.3±1.6 P (g/kg/d) 19.7±3.3 19.9±2.7 Weight gain similar in both groups (< fetal growth rate!) McLeod 2016. N=20/group: VLBW (<30 weeks), AGA Fortification based on assumed composition to target 3.8-4.4 g protein/kg.d & 130-150 kcal/kg.d. Weight gain similar in both groups (< fetal growth rate!) No difference in anthropometry and fat mass % at discharge

Adjustable protein fortification in VLBW infants N=32 VLBW ( 31weeks, 1400g) [RCT] (Arsanoglu 2006) HM+ std fortification bovine HMF (FM85) until D18 Then adjustable protein fortification ProMix (whey protein) according to blood urea level <3 mmol/l (9 mg/dl): +1 level of fortification > 5 mmol/l (14 mg/dl): -1 level of fortification 3-5 mmol/l (9-14 mg/dl): no change Based on bovine HMF (FM85) ± ProMix (whey prot: 0.3g/0.4g per g powder) Main outcome criteria: Weight gain

In summary, (pragmatic) fortification of HM Start Early : well-tolerated enteral intake at 50 to 80 ml/kg.d Multicomponent fortification (well-tolerated & efficient) Increase of fortified HM intake up to well-tolerated full-enteral feeding (160-180 ml/kg.d) Monitor Tolerance (digestive & metabolic) Weight gain Individualize fortification (monitor carefully postnatal growth) Targeted? If dedicated staff and infrared analyzer(s) Adjustable? Easier (no assessment of HM composition) and proven short-term efficacy on weight and HC growth

Evaluation of individualized nutritional care Population: Characteristics, growth Total (N=240) GA, weeks 29.2 ± 2.2 GA <28 wks, n (%) 80 (33) Birth weight, g 1230 ± 375 BW <-1DS, n (%) 49 (20) Antenatal steroids, n (%) 230 (96) Hospital stay, days 54 ± 23 GA at discharge, wks 37 ± 2 Body weight at discharge, g 2781 ± 478 Weight gain birth-discharge, g/kg.d 14.7 ± 2.3 EUGR*, n (%) 64 (27) EUGR= weight at discharge Z-score for age < -1 SD or change in Z-score between birth and discharge of more than 1 DS Croix Rousse hospital 2014-2017, Larcade J

Body weight, crown-heel length and head circumference Z-scores for age (mean±1sd) between birth and discharge in 240 VLBW infants. 1,5 1 0,5 0-0,5-1 -1,5-2 -2,5 Senterre 2011 (N=102), Birth: - 1.08 1.11 SD ; Discharge: - 1.33 0.86 SD NAISSANCE Birth J7 D7 J14 D14 J21 D21 J28 D28 J35 D35 J42 D42 SORTIE Discharge POIDS TAILLE PC Croix Rousse hospital 2014-2017, Larcade J

Fat mass (%) at discharge 30 N=80 24-28 weeks at 11 weeks of life 30 N=160 29-32 weeks at 6 weeks of life 25 25 20 20 15 15 10 10 5 5 0 Filles Garçons Filles Garçons Girls Boys Girls Boys Preterm infants at birth at 34-36 wks PCA (Hawkes 2011)* Term infants at 6-12 weeks of life (Carberry 2010)* 0 *assessed by Peapod Croix Rousse hospital 2014-2017, Larcade J

Nutrients intake during hospitalization 5 Protein intake (g/kg.d) 24-28 wks, 29-32 wks 4,5 4 3,5 3 180 160 140 120 J7 J14 J21 J28 J35 J42 Energy intake (Kcal/kg.d) 4,5 4 3,5 3 2,5 2 Protein/energy ratio (g/100 kcal) J7 J14 J21 J28 J35 J42 D7 D14 D21 D28 D35 D42 100 80 D7 D14 D21 D28 D35 D42 J7 J14 J21 J28 J35 J42 Croix Rousse hospital 2014-2017, Larcade J

CONCLUSION Available products allow individualized nutrition that could help to optimize the nutritional care of preterm infants fed human milk Strategy of HM fortification should be decided based on evidence and feasability (staff, organization) in each unit and based on a common policy unit

Thank you for your attention You are welcome! In Glasgow, UK October 5-6, 2017 European Milk Bank Association jean-charles.picaud@chu-lyon.fr

mosm/kg Prot. Int. (g/kg.d) Adjustable fortification: protein supplement (PS) (0,5-1 g/dl) Protein intake (for 160 ml/kg/d) & osmolality at H24 (mosm/kg) 500 Increased risk > 450 mosm/kg 400 300 5 4 3 2 1 LM + MCF1 4% + PS 0.5% LM + MCF1 4% + PS 1% LM + MCF2 4% + PS 0.5% LM + MCF2 4% + PS 1% LM + MCF3 3% + PS 0.5% LM + MCF3 3% + PS 1% LM + MCF3 4% + PS 0.5% LM + MCF3 4% + PS 1% MCF, multicomponent fortifier 1 (Suppletine), 2 (Fortipre), 3 (Aptamil)

Protein utilization in preterm and term infants N (mg) 700 600 500 400 N Intake N retention N urinary Preterm Term Intake Retention Urinary 300 200 100 PT-HM PTF1 PTF2 PTF3 PTF4 T-HM TF Adapted from: Putet 1984 1987, Rigo 1995-1999, Cooke 2006

After discharge: fortification of HM? N=39 BW 1300g, GA 29wks 50% of milk intake + fortifier 3 months after discharge No difference in breastfeeding duration LF+ WEIGHT LF At 12 months CA, weight, length, BMC LENGTH At 18 monts (n=27) Bayley II: no difference LF+ LF (O Connor 2008, Aimone 2009)

After discharge: fortification of HM? N=320, GA=24-32 wks, BW=535-2255g -HM Fortified (17.5 kcal & 1.4 g in 20-50 ml HM in feeding bottle or cup, once/d) Vs. Unfortified HM - PF (68 kcal & 2g) During 4 months after discharge Same duration of BF At 12 months CA: no difference in growth (Zacchariessen 2011)

Individualized targeted fortification of HM Multicomponent HMF + complementary fat Observational study 1 - Assessment of milk composition 2 - Energy fortification with Lipids Liquigen (1ml =0.5 g MCT) Aim: 4 g/100 ml 3 Addition of HM fortifier (Enfamil) Aim: 4,3 g Protein/kg.d 4 Analysis of milk composition Better weight gain Linear growth, HC: no effect Body composition?! De Halleux 2007

Targeted fortification (Rochow et al. 2013) Multicomponent HMF ± complementary fat / Protein / Carbohydrates Every 12 hours a hard job! «Nurses, neonatal research laboratory staff, dieteticians, physicians, nurse practitioners and technicians from nutrition services were involved» «Additional workload of 5-10 min per milk batch»

Adjustable protein fortification in VLBW infants Observational study Control Intervention (n=16) (n=15) GA, weeks 27.7 ± 0.98 27.1 ± 1 0.091 BW, g 992 ± 193 947 ± 141 0.353 Energy intake (Kcal/kg.day) 122 ± 9 117 ± 13 0.256 Protein intake (g/kg/d) 2.7 ± 0.2 4.0 ± 0.3 <0.0001 Weight velocity (g/kg.day) 20.4 ± 3.5 22.2 ± 4.7 0.192 Length velocity (mm/d) 1.1 ± 0.5 1.5 ± 0.6 0.04 HC velocity (mm/d) 0.9 ± 0.3 1.2 ± 0.2 0.004 mean ± SD Alan et al. Early Hum Dev 2013

Additional protein fortification in ELBW infants Picaud et al. JPGN 2016 Retrospective chart review N=152 ELBW infants (<1250 g) Croix Rousse hospital, Lyon 32% needed a protein suplement (entire protein) to reach a weight gain 20/kg.d Protein intake (g/kg.d) Prot./Cal. ratio (g/100 kcal) Wk 0 3,4 2,1 Wk 1 4,1 2,5 Wk 2 4,2 2,5 Median (min,max) Z-scores before and after additional protein supplementation ( ) Weight Length HC

Example of individual postnatal growth curves 27wks, 820g 27 wks 920 g 25 wks 780 g HOP. CROIX ROUSSE, LYON

Impact of breastfeeding / human milk Specific effect on health of preterm infants Short term (hospitalization) Adaptation to extrauterine life Hemodynamic (hypotension, persistent ductus arteriosus) Growth Digestive tolerance (necrotizing enterocolitis) Bronchopulmonary dysplasia Retinopathy Neurology (IVH, PVL, ROP, deafness) Infections (EOS, LOS) Parents-infant relationship Long term (infancy, adulthood) Respiratory (asthma) Neurological and cognitive (handicap, learning at school) Growth (final height, qualiy of growth) Metabolic et cardiovascular diseases Quality of life, parents-infant relationship

Postnatal growth & further development in preterm infants Weight gain during hospitalization Ehrenkranz 2006 cognitive development (2 years) Ehrenkranz et al. 2006 renal function (8 years) Bacchetta et al. 2009 FFM accretion during hospitalization associated with improved speed of processing in preterm infants. Pfister et al. 2013 associated with Improved neurodevelopment at 1 year CA for VLBW Infants. Ramel J Pediatr 2016