Hydrolyzed Proteins in Preterm Infants

Hydrolyzed Protein in Infant Feeding

Bhatia J, Shamir R, Vandenplas Y (eds): Protein in Neonatal and Infant Nutrition: Recent Updates. Nestlé Nutr Inst Workshop Ser, vol 86, pp 39–49, ( DOI: 10.1159/000444199 ) Nestec Ltd., Vevey/S. Karger AG., Basel, © 2016

Thibault Senterre · Jacques Rigo Department of Neonatology, Centre Hospitalier Régional de la Citadelle, CHU of Liège, University of Liège, Liège , Belgium

Abstract Milk proteins are an essential component of the diet of preterm infants who have high requirements. Hydrolyzed proteins (HPs) have been introduced in infants’ formulas (HPFs) to treat gastrointestinal disorders and to prevent allergic diseases. Several studies have evaluated the adequacy of HPs in preterm infants. Protein source significantly influences plasma amino acid concentrations. Protein utilization and efficiency are usually lower with HPFs compared to formulas with intact proteins. When protein intake is similar, a lower weight gain is generally observed with HPFs and a 10% increase in protein content is usually necessary to compensate for this reduction in protein utilization. Mineral absorption may also be reduced and no data exist for trace elements and vitamins. Most HPFs are associated with accelerated gastrointestinal transit time and softer stools but without clear benefit on feeding tolerance. Preterm infants seem to be at similar risk of allergic diseases than term infants, but the preventive effect of HPFs has not been sufficiently explored in preterm infants. Most modern HPFs designed for preterm infants are well tolerated and have adapted their nutrient content to improve nutrient absorption and retention. How- ever, their benefits and safety have not been demonstrated and, therefore, further high- quality studies are needed. © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel

Introduction

In preterm infants, nutritional support is critical to sustain adequate postnatal growth and development and long-term well-being to a level similar to those of term infants. Their expected growth rate and protein/amino acid (AA) turnover is very high compared to term infants and children, which explains their high nutritional requirements, especially for protein. During the last decades, great attention was focused on the importance of protein intake in order to reduce nutritional deﬁcits and postnatal growth restriction and to improve short- and long- term outcomes in preterm infants [1, 2] . Unfortunately, the immaturity of these infants exposes them to potentially severe postnatal diseases and many metabolic disorders. Thus, the range of optimal intakes is reduced in preterm infants due to the potential adverse effects of either insufficient or excessive AA concentrations. Therefore, both the quantity and the quality of protein intakes need to be considered when discussing preterm infants’ protein requirements [3] . Human milk (HM) represents the ‘gold standard’ in infant’s nutrition due to its important properties [4] . Recent proteomic evaluation of HM has revealed that it contains many species-specific proteins that are associated with the postnatal maturation and development of the gastrointestinal tract, the immune system and the brain [5–8] . When preterm infants cannot receive HM, they request specific preterm infant formulas (PTFs) produced according to several regulations and directives [9–11] . Many researches have been conducted to improve the protein profile and composition in infant formulas to mimic short- and long-term benefits of HM, in particular for hydrolyzed protein formulas (HPFs) [6, 12] . HPFs are processed by enzymatic hydrolysis of various protein sources, such as bovine casein/whey, soy and rice, followed by further processing, such as heat treatment and/or ultraﬁltration, or they are based on AA mixtures [12, 13] . They have been introduced many years ago in preterm infants as HM fortifiers [14, 15] or as elemental diets to treat intractable diarrhea [16] . Nowadays, HPFs are mainly used to treat allergic diseases and to prevent allergic sensitization in infants and toddlers [17–19] . They are also used to improve feeding tolerance and to reduce undesired gastrointestinal manifestations such as regurgitation, colics and/or constipation [19, 20]. However, industrial processes can significantly in- terfere with the bioavailability of the nitrogen content as well as the nutritional value of HPFs [12, 13, 21]. In addition, accumulating evidence has demonstrated the nutritional importance of the quality of the protein source for the postnatal maturation of the gastrointestinal tract in animal studies [19, 22, 23] . The objective of this review is to evaluate the nutritional adequacy of HPFs and their potential to improve feeding tolerance (gastrointestinal transit) and to reduce allergic diseases in preterm infants.

Nutritional Adequacy

The nutritional adequacy of a formula is usually assessed by the evaluation of growth rate (body weight, length and head circumference), metabolic balances (absorption rate, net utilization and efficiency) and biochemical parameters

40 Senterre · Rigo (plasma AA concentrations, blood urea nitrogen and prealbumin, for example) [12] . Several studies have been published on the nutritional adequacy of HPFs in preterm infants. Some of them concerned experimental HPFs given to a small number of infants and only focused on some aspects of nutritional adequacy. In the early 1990s, Rigo et al. [12] and Rigo and Senterre [24] performed a 3-day metabolic balance trial to evaluate plasma AA profiles with different types of HPFs: 100% whey (n = 7), 78% whey and 22% casein (n = 7), and 78% whey and 22% casein enriched with histidine (n = 5). A control group was fed a standard PTF (sPTF) with intact proteins (n = 39). Both nitrogen absorption and efficacy were significantly decreased with HPFs (83 and 64%, respectively) compared to the control group (90 and 70%, respectively). Mineral absorption was also lower, especially for phosphorus. The plasma AA profile differed significantly from that of infants fed HM or sPTF. It mainly depended on the protein source and was related to the AA content of the formula [12, 24]. Plasma threo- nine concentration was increased, whereas plasma tyrosine, histidine and tryp- tophan concentrations were significantly decreased in the HPFs without supple- mentation [12, 24] . Following these studies, HPFs have been improved by the selection of the protein source (formulas containing various whey:casein ratios and acidic whey instead of sweet whey), by an increased protein content (i.e. protein:energy ratio), by the addition of some individual AAs to correct the AA imbalance and by improved hydrolysis technologies. In addition, mineral retention was also improved by increasing calcium and phosphorus contents in HPFs and by the selection of minerals with higher bioavailability. In 1999, Mihatsch and Pohlandt [25] compared an experimental HPF (60/40 whey/casein ratio) with a sPTF in a 5-day crossover trial (n = 15). This experimental HPF had higher protein (12%), energy (15%), calcium (34%) and phosphorus (46%) contents to counteract the reduced absorption rates. During the short period of study, the growth rate was similar. Only little differences in plasma AA profiles were observed and AA profiles were considered globally similar. Blood urea concentration was higher with the HPF in relation to the increase in nitrogen content [25] . In 2001, Szajewska et al. [26] evaluated extensively HPF (eHF; n = 16) and partially HPF (pHF; n = 15) during a 12-week period. There were two control groups: one fed fortified HM (n = 15) and one fed a sPTF (n = 15). Compared to the sPTF, protein contents were 9 and 14% higher in the eHF and pHF, respectively. Weight gain tended to be lower in infants fed the HPF compared to the sPTF, with a mean difference in weight gain of –4.7 g/day (eHF) and –2.8 g/day (pHF) during the first 4 weeks and –2.0 and –1.3 g/day, respectively, during the 12-week study period. Due to the limited number of infants, these differences were not significant. Nevertheless, considering the higher protein

Hydrolyzed Proteins in Preterm Infants 41 content in the HPFs, the nutritional efficacy seems in favor of the sPTF and noninferiority could not be demonstrated for the HPFs. In this study, the plasma AA profile of the HPFs appears to be similar to that of the sPTF, but it differs from that of the fortified HM group. In a longitudinal study (8 weeks), Picaud et al. [27] evaluated another experimental pHF (skim milk mixture of acid and rennet whey) in very preterm infants (n = 9). The control group was fed a sPTF (n = 7). This study confirmed that nitrogen absorption was significantly lower with the HPF (83 vs. 89%). They also confirmed that average protein content should be 10% higher in HPFs to obtain similar protein absorption than with sPTFs. AA profiles were similar (same protein source) and both were within the normal range. At theoretical term, body weight was significantly lower in the HPF group than in the sPTF group. That difference was the result of a significantly lower weight gain from study inclusion to discharge in infants fed the HPF compared with those fed the sPTF (28.1 ± 5.1 vs. 32.8 ± 2.4 g/day, respectively; p = 0.03). In 2005, Maggio et al. [28] compared a HPF (100% acid whey, n = 10) to a sPTF (51% sweet whey/49% casein, n = 11) with similar protein content (2.7 g/100 kcal). A slower weight gain (17.4 ± 3.4 vs. 20.5 ± 3.3 g/kg/day, respectively; p = 0.045) was observed with the HPF as well as a lower change in the z- scores for weight (–0.18 ± 0.16 vs. 0.00 ± 0.09; p = 0.009) and head circumference (–0.06 ± 0.13 vs. 0.06 ± 0.13; p = 0.049). In that study, a signiﬁcantly higher urinary excretion of essential AAs was also reported after 14 days in the HPF group, suggesting a decrease in protein efficiency with the HPF. In 2006, Cooke et al. [29] evaluated two HPFs with two different protein contents (3.6 and 3.0 g/100 kcal) in a 1-week crossover trial. They reported a nitrogen absorption rate of 83 and 84%, respectively, i.e. a value similar to that generally reported with HPF. Weight gain, blood urea nitrogen, retinol binding protein and plasma AA concentrations were higher in the group receiving the HPF with the high protein content (3.6 g/100 kcal). In 2009, Florendo et al. [30] evaluated a pHF during a 3-week period (n = 42); the control group received an sPTF (n = 38). Growth (weight, length and head circumference gain) was similar between the two groups that received similar protein and energy intakes. Plasma AA profiles were similar, but several differences were observed in serum biochemistries although all were within the normal range. Blood urea was higher with the HPF while total serum protein and albumin were lower. In addition, blood calcium and phosphorus concentrations were lower with the HPF at the end of the study, but no difference was observed for alkaline phosphatase [30] . More recently, Cooke et al. [31] compared two pHFs containing 3.0 and 3.6 g of protein per 100 kcal. No differences were detected in weight gain, body weight

42 Senterre · Rigo Table 1. Comparison of weight gain (g per day) between preterm infants fed HPF and sPTF

First author HPF sPTF p value Comments

Szajewska [26] 27.2±8.5 31.90±12.9 n.s. eHF with 9% higher protein content (2001) (n = 16 vs. 15 during 4 weeks) 32.2±5.7 34.22±4.7 n.s. eHF with 9% higher protein content (n = 16 vs. 15 during 12 weeks) 29.1±5.7 31.9±12.9 n.s. pHF with 5% higher protein content (n = 15 vs. 15 during 4 weeks) 32.9±5.1 34.22±4.7 n.s. pHF with 5% higher protein content (n = 15 vs. 15 during 12 weeks) Picaud [27] (2001) 21.9±2.11 23.0±2.01 n.s. Similar protein content (n = 9 vs. 7 during 7 days) 28.1±5.1 32.8±2.4 0.03 Similar protein content (n = 9 vs. 7 during 8 weeks) Maggio [28] (2005) 17.4+3.41 20.5+3.31 0.045 Similar protein content (n = 10 vs. 9 during 4 weeks) Florendo [30] 27.4±8.3 28.1±4.3 n.s. Similar protein content (2009) (n = 38 vs. 34 during 3 weeks)

1 Weight gain units = g/kg per day.

or weight z-scores, but in both groups z-scores remained in parallel to those in utero. In addition, length z-scores were greater in infants fed the high protein content formula (p < 0.05). As the study progressed, length z-scores did not change in infants fed the high protein content formula, closely paralleling scores in utero, but decreased significantly in infants fed the low protein content formula (p < 0.0001) [31]. This study suggests that a high protein content (high protein/energy ratio, 3.6 g/100 kcal) in pHF promotes linear growth by improv- ing the lean body mass accretion rate. However, this improvement in linear growth and lean body mass accretion in preterm infants requires confirmation. In summary, most of these studies showed that the use of HPFs instead of sPTF with similar protein content induced a slower weight gain ( table 1 ) due to a lower nitrogen/protein absorption rate. The lower nutritional efficiency of the HPFs implies that an average increase of 10% in protein content within HPFs is necessary to induce protein retention similar to that with sPTF made with intact proteins. Initial studies showed that the protein source of HPFs significantly influenced the plasma AA profile but most AA imbalances have been corrected in recent HPFs. Mineral absorption may also be decreased with HPFs compared to sPTFs, but the quality of the mineral source had a higher

Hydrolyzed Proteins in Preterm Infants 43 impact on the absorption rate than the protein source. No data exist concern- ing the influence of HPFs on trace elements and vitamin absorption. Finally, recent proteomic studies on HM and cow milk proteins as well as the effect of bioactive peptides produced during digestion of HM and formula [5–8] suggest that further research is needed before promoting the use of HPFs in preterm infants.

Gastrointestinal Transit Time and Feeding Tolerance

Preterm infants frequently suffer from some kind of feeding intolerance, and necrotizing enterocolitis always represents a dramatic complication in these infants. The definition of feeding intolerance is not clear in preterm infants but many efforts have been made to reduce the incidence and the severity of gastrointestinal symptoms such as gastric residuals, regurgitation/spitting, abdominal distension and constipation [32] . In 2007, Szajewska [33] reviewed the effect of HPFs on feeding tolerance in three studies. In the study by Riezzo et al. [34], no difference was observed between infants fed HPF (n = 18) or sPTF (n = 18) although regurgitation and vomiting were very frequent (64 and 78%, respectively). In addition, no differences were found in terms of gastric electrical activity and gastric emptying time between the two groups [34]. In the study by Mihatsch et al. [35] , HPF was well tolerated with similar vomiting/spitting and similar gastric residuals. The number of stools was similar, but soft stools were more frequently reported with HPF. Gastrointestinal transit time was also shorter: 9.8 versus 19 h on average (range 5–20.8 vs. 6–66) [35] . In a separate publication [36] , theses authors showed that in infants with very low birth weight fed HPF the time to establish full enteral feeding was significantly decreased compared to those fed sPTF (mean reduction: 2 days, i.e. 10 vs. 12 , range 9–27 vs. 9–28 days; p = 0.0024). In her review, Szajewska [33] concluded that despite some potential clinical advan- tages, like shorter time to achieve full feeding, it is unclear whether the use of HPFs should be adopted as routine practice because of its limited information regarding nutritional adequacy. In addition to these studies, Picaud et al. [27] showed that HPF was well tolerated and no difference was observed for the occurrence of vomiting and in the volume of gastric residuals. Gastrointestinal transit time was shorter with HPF in their study (mean: 18 ± 4 vs. 25 ± 10 h) [27] . In the study by Maggio et al. [28] , HPF was also well tolerated with similar vomiting/spitting and similar gastric residuals. In the study by Florendo et al. [30] , feeding tolerance was excellent and no difference was observed between HPF and sPTF.

44 Senterre · Rigo Recently, Corvaglia et al. [37] evaluated the effect of eHF on symptoms of both gastroesophageal reflux (frequent regurgitation and/or postprandial de- saturation) and feeding intolerance (large gastric residuals, abdominal distension and constipation) using a crossover design (n = 18). They were unable to demonstrate any effect of the HPF on gastrointestinal symptoms and on multi- channel intraluminal impedance monitoring. Besides, they showed a reduction in gastroesophageal reflux episodes detected by pH monitoring [37]. In a letter to the editor, it was suggested that this effect on esophageal pH was mainly due the buffering effect of HPF on gastric pH explaining the absence of an effect observed with impedance monitoring [38] . In summary, HPFs improved feeding tolerance and are usually associated with accelerated gastrointestinal transit time and softer stools. However, HPFs do not seem to reduce feeding intolerance symptoms although time to achieve full enteral feeding was reduced in a study in very preterm infants. This potential benefit needs to be further confirmed by high-quality randomized controlled trials.

Prevention of Allergic Diseases

Preterm infants have increased intestinal permeability and higher food antigen uptake [39] . As it is combined with immature immune functions, it has led some authors to consider preterm infants at higher risk of food allergy [40, 41] . Some studies have suggested that preterm infants may more frequently develop recurrent wheezing and symptoms of asthma [42, 43]. However, there is some debate about considering all wheezing manifestations as allergic diseases in former preterm infants [44, 45] . These symptoms may be more frequently related to per- sistent bronchial hyperreactivity due to bronchopulmonary dysplasia rather than real allergic diseases [46, 47] . Up to now, there is no evidence demonstrat- ing any difference in the rate of food allergy and other allergic diseases in preterm infants compared to term infants [48–54] . By contrast, some authors even pointed out that prematurity may be associated with less allergic sensitization in children as early exposure to an antigen would favor tolerance and lower the risk of sensitization [55, 56] . In a large randomized controlled trial (n = 777), Lucas et al. [49] did not find any difference in the incidence of allergic reactions after 18 months in preterm infants fed bank donor HM or sPTF. In very preterm infants (n = 62), Kwinta et al. [46] evaluated the effect of eHF on the incidence of atopic diseases and mark- ers of allergy at 5–7 years of age. They were not able to suggest any benefit of a 1-month intervention in their unselected cohort of preterm infants [46] .

Hydrolyzed Proteins in Preterm Infants 45 A variety of factors are known to influence the risk of allergic diseases, such as family history, and allergen and environmental exposure (atmospheric pollution, passive tobacco smoke, house dust and urban residency) [57] . In preterm infants, it has also been confirmed that familial predisposition to allergic diseases significantly increases the risk of atopic dermatitis and recurrent wheezing [49, 54] . One study evaluated whether the use of pHF (n = 32) or eHF (n = 26) until 4–5 months of age may prevent allergic disease in preterm infants with familial allergic predispositions [58]. Two control groups were included in the study, one receiving sPTF (n = 32) and one receiving HM (n = 32). In this study, the over- all incidence of allergic diseases at both 4–5 and 12 months of age and prevalence of total IgE and/or cow’s milk protein-specific IgE levels did not differ. Besides, the eHF had a high rate of nonacceptance (23%) leading to a significant propor- tion of infants fed the eHF who were no longer part of the per-protocol analysis at 4–5 and 12 months of life. Nevertheless, the intention-to-treat analysis showed that the risk of atopic dermatitis by 12 months of age was significantly reduced in the eHF group [58] . In summary, prematurity does not seem to induce a higher risk of developing allergic diseases in later life. As for term infants, a family history of allergic diseases is also the main risk factor for developing allergic diseases in preterm infants. Further studies are needed to evaluate the role of HPFs in the prevention of later allergic diseases in preterm infants, especially in neonates with a family history of allergy.

Conclusion

Breastfeeding, own mother milk and banked donor HM remain the best source of nutrients for preterm infants. When HM is not available, sPTFs are required to meet the high requirements of these infants. HPFs are well tolerated by preterm infants and harmful effects of modern HPFs for preterm infants have not been reported. However, most studies have demonstrated that their nutritional value is usually lower than that of intact protein formulas, indicating that a higher protein content is necessary to allow for similar protein retention rates. Simi- larly, a higher mineral content is also frequently required. Potential clinical benefits on feeding tolerance have not been clearly demonstrated. Further high-quality studies including a large number of infants are necessary to demonstrate the nutritional noninferiority of HPFs compared to modern intact protein formulas in preterm infants. These studies should also evaluate potential consequences on gastrointestinal functions, on the incidence of infections and necrotizing enterocolitis, and on immune, metabolic and hormonal long-term outcomes.

46 Senterre · Rigo Disclosure Statement

T. Senterre has participated as a speaker for Nestlé, Nutricia and Mead Johnson Nutri- tion, and J. Rigo as a clinical investigator, advisory board member or speaker for Mead Johnson Nutrition, Danone, Nestlé and Nutricia.

References

1 Senterre T, Rigo J: Optimizing early nutri- 10 Klein CJ: Nutrient requirements for preterm

tional support based on recent recommenda- infant formulas. J Nutr 2002; 132(6 suppl 1): tions in VLBW infants and postnatal growth 1395S–1577S. restriction. J Pediatr Gastroenterol Nutr 11 Koletzko B, Poindexter B, Uauy R: Recom-

2011; 53: 536–542. mended nutrient intake levels for stable, fully 2 Maas C, Poets CF, Franz AR: Avoiding post- enterally fed very low birth weight infants.

natal undernutrition of VLBW infants during World Rev Nutr Diet 2014; 110: 297–299. neonatal intensive care: evidence and person- 12 Rigo J, Salle BL, Picaud JC, et al: Nutritional al view in the absence of evidence. Arch Dis evaluation of protein hydrolysate formulas.

Child Fetal Neonatal Ed 2015; 100:F76–F81. Eur J Clin Nutr 1995; 49(suppl 1):S26–S38. 3 Rigo J: Protein, amino acids and other nitro- 13 Wada Y, Lönnerdal B: Effects of different in- gen compounds; in Tsang RC, Uauy R, dustrial heating processes of milk on site-spe- Koletzko B, Zlotkin SH (eds): Nutrition of cific protein modifications and their relation- the Preterm Infant. Cincinnati, Digital Edu- ship to in vitro and in vivo digestibility. J

cating Publishing, 2005, pp 45–80. Agric Food Chem 2014; 62: 4175–4185. 4 Breastfeeding and the use of human milk. 14 Jorpes JE, Magnusson JH, Wretlind A: Casein

Section on breastfeeding. Pediatrics 2012; hydrolysate; a supplementary food for pre-

129:e827–e841. mature infants. Lancet 1946; 2: 228–232. 5 Beck KL, Weber D, Phinney BS, et al: Com- 15 Magnusson JH: An amino acid mixture, ca- parative proteomics of human and macaque sein hydrolysate, as an additional food for

milk reveals species-specific nutrition during premature infants. Acta Paediatr 1948;

postnatal development. J Proteome Res 2015; 35(suppl 1):290.

14: 2143–2157. 16 Scott JP, Kety JG: Experiences with epidemic 6 Lonnerdal B: Infant formula and infant nutri- diarrhea of the newborn; the use of nutrami- tion: bioactive proteins of human milk and gen in its dietary management. J Pediatr

implications for composition of infant for- 1948; 33: 573–577.

mulas. Am J Clin Nutr 2014; 99: 712S–717S. 17 Alexander DD, Cabana MD: Partially hydro- 7 Hettinga K, van Valenberg H, de Vries S, et lyzed 100% whey protein infant formula and al: The host defense proteome of human and reduced risk of atopic dermatitis: a meta-

bovine milk. PLoS One 2011; 6:e19433. analysis. J Pediatr Gastroenterol Nutr 2010;

8 Lönnerdal B: Human milk: bioactive pro- 50: 422–430. teins/peptides and immunological properties; 18 Koletzko S, Niggemann B, Arato A, et al: Di- in Bhatia J, Shamir R, Vandenplas Y (eds): agnostic approach and management of cow’s- Protein in Neonatal and Infant Nutrition: milk protein allergy in infants and children: Recent Updates. Nestlé Nutr Inst Workshop ESPGHAN GI Committee practical guide-

Ser. Basel, Karger 2016, vol 86, pp 97–107. lines. J Pediatr Gastroenterol Nutr 2012; 55: 9 Agostoni C, Buonocore G, Carnielli VP, et al: 221–229. Enteral nutrient supply for preterm infants: 19 Vandenplas Y, Alarcon P, Fleischer D, et al: commentary from the European Society of Should partial hydrolysates be used as starter Paediatric Gastroenterology, Hepatology and infant formula? A working group consensus.

Nutrition Committee on Nutrition. J Pediatr J Pediatr Gastroenterol Nutr 2016; 62: 22–35.

Gastroenterol Nutr 2010; 50: 85–91.

Hydrolyzed Proteins in Preterm Infants 47 20 Vandenplas Y, Cruchet S, Faure C, et al: 31 Cooke R, Embleton N, Rigo J, et al: Dietary When should we use partially hydrolysed for- protein in the very-low-birth-weight infants: mulae for frequent gastrointestinal symptoms multicenter randomized controlled trial to

and allergy prevention? Acta Paediatr 2014; evaluate the effects of dietary protein level on

103: 689–695. growth. Arch Dis Child Fetal Neonatal Ed

21 Schaafsma G: Safety of protein hydrolysates, 2014; 99(S2):A57. fractions thereof and bioactive peptides in 32 Senterre T: Practice of enteral nutrition in

human nutrition. Eur J Clin Nutr 2009; 63: very low birth weight and extremely low birth

1161–1168. weight infants. World Rev Nutr Diet 2014;

22 Kinouchi T, Koyama S, Harada E, et al: Large 110: 201–214. molecule protein feeding during the suckling 33 Szajewska H: Extensive and partial protein period is required for the development of hydrolysate preterm formulas. J Pediatr Gas-

pancreatic digestive functions in rats. Am J troenterol Nutr 2007; 45(suppl 3):S183–S187.

Physiol Regul Integr Comp Physiol 2012; 34 Riezzo G, Indrio F, Montagna O, et al: Gas- 303:R1268–R1276. tric electrical activity and gastric emptying in 23 Comstock SS, Reznikov EA, Contractor N, et preterm newborns fed standard and hydroly- al: Dietary bovine lactoferrin alters mucosal sate formulas. J Pediatr Gastroenterol Nutr

and systemic immune cell responses in neo- 2001; 33: 290–295.

natal piglets. J Nutr 2014; 144: 525–532. 35 Mihatsch WA, Hogel J, Pohlandt F: Hydro- 24 Rigo J, Senterre J: Metabolic balance studies lysed protein accelerates the gastrointestinal and plasma amino acid concentrations in transport of formula in preterm infants. Acta

preterm infants fed experimental protein hy- Paediatr 2001; 90: 196–198. drolysate preterm formulas. Acta Paediatr 36 Mihatsch WA, Franz AR, Hogel J, et al: Hy-

Suppl 1994; 405: 98–104. drolyzed protein accelerates feeding advance- 25 Mihatsch WA, Pohlandt F: Protein hydroly- ment in very low birth weight infants. Pediat-

sate formula maintains homeostasis of plas- rics 2002; 110: 1199–1203. ma amino acids in preterm infants. J Pediatr 37 Corvaglia L, Mariani E, Aceti A, et al: Exten-

Gastroenterol Nutr 1999; 29: 406–410. sively hydrolyzed protein formula reduces 26 Szajewska H, Albrecht P, Stoitiska B, et al: acid gastro-esophageal reflux in symptomatic

Extensive and partial protein hydrolysate preterm infants. Early Hum Dev 2013; 89: preterm formulas: the effect on growth rate, 453–455. protein metabolism indices, and plasma ami- 38 Cresi F, Maggiora E, Bertino E: Buffering ef- no acid concentrations. J Pediatr Gastroen- fect of hydrolyzed protein formula on gastric

terol Nutr 2001; 32: 303–309. pH. Early Hum Dev 2013; 89: 845–846. 27 Picaud JC, Rigo J, Normand S, et al: Nutri- 39 Kuitunen OO, Savilahti E, Sarnesto A: Hu- tional efficacy of preterm formula with a par- man alpha-lactalbumin and bovine beta-lac- tially hydrolyzed protein source: a random- toglobulin absorption in premature infants.

ized pilot study. J Pediatr Gastroenterol Nutr Pediatr Res 1994; 35: 344–347.

2001; 32: 555–561. 40 Taylor B, Norman AP, Orgel HA, et al: Tran- 28 Maggio L, Zuppa AA, Sawatzki G, et al: sient IgA deficiency and pathogenesis of in-

Higher urinary excretion of essential amino fantile atopy. Lancet 1973; 2: 111–113. acids in preterm infants fed protein hydroly- 41 McNeish AS: Enzymatic maturation of the

sates. Acta Paediatr 2005; 94: 75–84. gastrointestinal tract and its relevance to food 29 Cooke R, Embleton N, Rigo J, et al: High pro- allergy and intolerance in infancy. Ann Al-

tein pre-term infant formula: effect on nutri- lergy 1984; 53: 643–648. ent balance, metabolic status and growth. Pe- 42 Elder DE, Hagan R, Evans SF, et al: Recurrent

diatr Res 2006; 59: 265–270. wheezing in very preterm infants. Arch Dis

30 Florendo KN, Bellflower B, van Zwol A, et al: Child Fetal Neonatal Ed 1996; 74:F165–F171. Growth in preterm infants fed either a par- 43 Dombkowski KJ, Leung SW, Gurney JG: Pre- tially hydrolyzed whey or an intact casein/ maturity as a predictor of childhood asthma whey preterm infant formula. J Perinatol among low-income children. Ann Epidemiol

2009; 29: 106–111. 2008; 18: 290–297.

48 Senterre · Rigo 44 Martinez FD, Wright AL, Taussig LM, et al: 52 de Martino M, Donzelli GP, Galli L, et al: Asthma and wheezing in the first six years of Food allergy in preterm infants fed human

life. The Group Health Medical Associates. N milk. Biol Neonate 1989; 56: 301–305.

Engl J Med 1995; 332: 133–138. 53 Liem JJ, Kozyrskyj AL, Huq SI, et al: The risk 45 Wennergren G, Amark M, Amark K, et al: of developing food allergy in premature or Wheezing bronchitis reinvestigated at the age low-birth-weight children. J Allergy Clin Im-

of 10 years. Acta Paediatr 1997; 86: 351–355. munol 2007; 119: 1203–1209. 46 Kwinta P, Sawiec P, Klimek M, et al: Correla- 54 Zachariassen G, Faerk J, Esberg BH, et al: tion between early neonatal diet and atopic Allergic diseases among very preterm infants symptoms up to 5–7 years of age in very low according to nutrition after hospital dis-

birth weight infants: follow-up of random- charge. Pediatr Allergy Immunol 2011; 22: ized, double-blind study. Pediatr Allergy Im- 515–520.

munol 2009; 20: 458–466. 55 Siltanen M, Kajosaari M, Savilahti EM, et al: 47 Greenough A: Long-term pulmonary out- IgG and IgA antibody levels to cow’s milk are come in the preterm infant. Neonatology low at age 10 years in children born preterm.

2008; 93: 324–327. J Allergy Clin Immunol 2002; 110: 658–663. 48 Savilahti E, Tuomikoski-Jaakkola P, Jarven- 56 Buhrer C, Grimmer I, Niggemann B, et al: paa AL, et al: Early feeding of preterm infants Low 1-year prevalence of atopic eczema in

and allergic symptoms during childhood. very low birthweight infants. Lancet 1999;

Acta Paediatr 1993; 82: 340–344. 353: 1674. 49 Lucas A, Brooke OG, Morley R, et al: Early 57 Halken S: Prevention of allergic disease in diet of preterm infants and development of childhood: clinical and epidemiological as- allergic or atopic disease: randomised pro- pects of primary and secondary allergy pre-

spective study. BMJ 1990; 300: 837–840. vention. Pediatr Allergy Immunol 2004; 50 Siltanen M, Kajosaari M, Pohjavuori M, et al: 15(suppl 16):4–5, 9–32. Prematurity at birth reduces the long-term 58 Szajewska H, Mrukowicz JZ, Stoinska B, et al:

risk of atopy. J Allergy Clin Immunol 2001; Extensively and partially hydrolysed preterm

107: 229–234. formulas in the prevention of allergic diseases 51 Hikino S, Nakayama H, Yamamoto J, et al: in preterm infants: a randomized, double-

Food allergy and atopic dermatitis in low blind trial. Acta Paediatr 2004; 93: 1159–1165. birthweight infants during early childhood.

Acta Paediatr 2001; 90: 850–855.

Hydrolyzed Proteins in Preterm Infants 49