Parenteral nutrition

During the initial days or weeks of life, GIT impairment in LBW infants usually induces an inability to tolerate enteral feedings, which can be referred to as ‘feeding intolerance’, as indicated by increased gastric residuals, abdominal distension and/or emesis⁽ Reference Fanaro ^{54 )}. In this case, parenteral nutrition (PN), supplying essential nutrients either by a central or peripheral intravenous injection⁽ Reference Ziegler, Thureen and Carlson ^{55 ,} Reference Heird ^{56 )}, is considered a useful strategy to avoid feeding intolerance until full enteral nutrition (EN) can be adopted. PN should be started either immediately after birth or within the first 2 h of life⁽ Reference Prince and Groh-Wargo ^{57 )}. In addition, Valentine et al.⁽ Reference Valentine, Fernandez and Rogers ^{58 )} reported that when PN started within the first 24 h of life, these small infants had shorter durations of PN administration and achieved full enteral feedings earlier compared with those that started PN more than 24 h after birth. The early use of PN has been shown to reduce postnatal growth failure and mortality, prevent N imbalance, prevent essential fatty acid and trace mineral deficiency, and improve growth and neurodevelopmental outcomes⁽ Reference Patel and Bhatia ^{59 )}, without the associated short-term metabolic or clinical side effects⁽ Reference Moyses, Johnson and Leaf ^{60 )}. In early intravenous nutrition for very low birth weight (VLBW; birth weight <1500 g) infants, the recommended administrations of amino acids, glucose and lipids are 2·5–3·5, 12–18 and 3 g/kg per d, respectively. The reasonable levels of Na, K, Cl, Ca, P and Mg are assumed to be 3–5 , 1–2, 2–3, 75–90, 60–67 and 7·5–10·5 mg/kg per d, respectively⁽ Reference De Curtis and Rigo ^{61 )}.

In total PN of infants, glucose is the most widely used intravenous carbohydrate for neonates because it is a main energy source and is readily available to the brain. Many other non-glucose carbohydrates such as fructose, galactose, sorbitol, glycerol and ethanol have been used as sources of carbohydrates. However, their effects are considered inferior to glucose⁽ Reference Patel and Bhatia ^{59 )}. Commercial lipid emulsions generally include soyabean oil, mixtures of olive and soyabean oils and mixtures of olive and fish oils⁽ Reference Patel and Bhatia ^{59 )}; the fish oil-based lipid emulsion may be a more effective source⁽ Reference Gura, Lee and Valim ^{62 ,} Reference de Meijer, Gura and Le ^{63 )}.

Enteral nutrition

Enteral feeding is the preferred pattern of nutrition provision for LBW infants. Human milk is not only the paramount EN source but also a supplier of various bioactive compounds to infants, which play vital roles in regulating GIT development and protection from infections⁽ Reference Wu, Wang and Wu ^{64 )}. However, it can be accompanied by side effects including feeding intolerance and other aforementioned complications. A combination of PN and EN is commonly practiced after birth until full EN can be accomplished⁽ Reference Prince and Groh-Wargo ^{57 )}. Once full feedings have been established and PN has been terminated, EN is fully responsible for providing all nutrients to support normal growth⁽ Reference Ziegler ^{65 )}. Considering that the maternal milk from preterm mothers provides inadequate quantities of nutrients⁽ Reference Kuschel and Harding ^{66 )}, especially protein⁽ Reference De Curtis and Rigo ^{61 ,} Reference Kuschel and Harding ^{66 )}, targeted human-milk fortifiers are added to either the maternal or the donor milk to meet the nutritional needs of rapidly growing LBW infants⁽ Reference Groh-Wargo and Sapsford ^{67 )}. It can be advised to supply a fortifier content of up to 1·3 g of protein/100 ml for these small infants, beginning from the time they can tolerate 50–70 ml/kg per d of milk⁽ Reference De Curtis and Rigo ^{61 )}. Tolerance formulas including soya-protein, protein-hydrolysate and amino-acid-based formulas can be utilised to promote feeding tolerance in LBW neonates⁽ Reference Prince and Groh-Wargo ^{57 )}.

In preterm formulas, as a reference for LBW infants, the carbohydrate source is a combination of lactose and sucrose⁽ Reference Hay and Hendrickson ^{68 )}, considering the inadequate lactase activity of the GIT⁽ Reference Tan-Dy and Ohlsson ^{69 )}. A part of the sucrose or lactose in formula could be replaced by easily digestible glucose polymers to ensure low osmolality of formulas⁽ Reference De Curtis and Rigo ^{61 ,} Reference Hay and Hendrickson ^{68 )}. The protein sources are whey and casein derived from cows’ milk, and sometimes soya protein. In addition, the fat source is a mixture of vegetable oils containing 30–40 % medium-chain TAG in lipids to improve fat absorption⁽ Reference De Curtis and Rigo ^{61 ,} Reference Hay and Hendrickson ^{68 )}.

Continuous and intermittent bolus feeding

Compared with continuous feeding, intermittent bolus feeding is considered to be more effective in shortening the time to establish full enteral feeding, improving feed tolerance and accelerating weight gain in premature LBW infants⁽ Reference Dollberg, Kuint and Mazkereth ^{70 ,} Reference Schanler, Shulman and Lau ^{71 )}. Using the newborn NBW pig as a model, it has been demonstrated that intermittent bolus feeding increases protein synthesis to a greater extent than continuous feeding by improving activation of amino acids and insulin-induced translation initiation⁽ Reference Gazzaneo, Suryawan and Orellana ^{72 ,} Reference El-Kadi, Gazzaneo and Suryawan ^{73 )}. On the other hand, contradictory results have also been reported⁽ Reference Premji and Chessell ^{74 ,} Reference Dsilna, Christensson and Alfredsson ^{75 )}. This observation in pigs would also be useful to provide some implications for clinical practice in LBW infants. Dsilna et al.⁽ Reference Dsilna, Christensson and Gustafsson ^{76 )} demonstrated that continuous feeding could contribute to reduced behavioural stress response compared with intermittent bolus feeding among premature VLBW infants. In spite of these data, it is still difficult to recommend either method of gavage feeding, and more trials in LBW infants or animals are needed to evaluate the benefits and side effects of both methods.

Functional amino acids and derivatives

Epidemiological and metabolic studies have provided novel insights into alterations in the amino acid profiles in LBW fetuses and neonates. Reduction in the concentrations of the arginine (Arg) family of amino acids (Arg, proline, citrulline, glutamine (Gln)) have been reported in the umbilical vein plasma of fetuses or in the plasma of LBW newborns in humans⁽ Reference Sanz-Cortes, Carbajo and Crispi ^{103 –} Reference Tea, Le Gall and Küster ^{105 )}, pigs⁽ Reference Wang, Zhang and Zhou ^{11 ,} Reference He, Ren and Kong ^{34 ,} Reference Lin, Liu and Feng ^{106 ,} Reference Wu, Bazer and Johnson ^{107 )} and rats⁽ Reference Alexandre-Gouabau, Courant and Le Gall ^{108 )}. Branched-chain amino acids (BCAA) (leucine, isoleucine, valine) also show lower levels in the plasma of fetuses and neonates born with LBW⁽ Reference He, Ren and Kong ^{34 ,} Reference Sanz-Cortes, Carbajo and Crispi ^{103 ,} Reference Tea, Le Gall and Küster ^{105 ,} Reference Lin, Liu and Feng ^{106 )}. All of the above implicate that these functional amino acids could be used as potential biomarkers for designing effective strategies to improve the outcomes in LBW neonates.

l-Arginine

l-Arginine (Arg) is an essential amino acid for the maximal growth of young mammals⁽ Reference Flynn, Meininger and Haynes ^{109 –} Reference Southern and Baker ^{111 )}. It is an essential precursor for the biological synthesis of important molecules such as glutamate, ornithine, proline, polyamines, creatinine, nitric oxide and agmatine⁽ Reference Flynn, Meininger and Haynes ^{109 ,} Reference Wu, Knabe and Kim ^{112 –} Reference Wu and Morris ^{114 )}.

A systematic review derived from eighty-three human studies reported that the concentration of Arg was about 0·94 g/l in preterm transitional milk⁽ Reference Zhang, Adelman and Rai ^{115 )}, and the mean milk yield of preterm mothers at 6 weeks postpartum was approximately 541(SD460·9) ml/d⁽ Reference Hill, Aldag and Chatterton ^{116 )}. Therefore, provision of Arg from milk is far from adequate to meet the high requirements of growth and metabolic function in preterm newborns⁽ Reference Tomlinson, Rafii and Sgro ^{117 )}. Dietary supplementation of 0·6 % Arg to LBW piglets from 7 to 14 d of age resulted in increased average daily gain and daily DM⁽ Reference Wang, Zhang and Zhou ^{11 )}. The incidence of diarrhoea dropped by 61·5 %, accompanied by increased small intestine weight and mucosal villus height⁽ Reference Wang, Zhang and Zhou ^{11 )}. Notably, Arg supplementation was found to effectively reduce the incidence of necrotising enterocolitis (NEC) in premature infants with LBW⁽ Reference Neu ^{118 –} Reference Shah and Shah ^{120 )}. In addition, a recent study observed daily dosing of Arg (145·0 mg/kg body weight per administration) to LBW piglets, from 1 to 17 d after birth, had an ability to revert some of the abnormalities involving amino acids, energy, lipid and nucleotide (NT) metabolism caused by LBW⁽ Reference Getty, Almeida and Baratta ^{121 )}. However, these effects appear to be independent of the growth-regulation system because reduced growth rate is still present in these piglets⁽ Reference Getty, Almeida and Baratta ^{121 )}. Therefore, optimisation of Arg dosage and timing should be investigated to achieve desirable effects in LBW neonates.

Glutamine

Gln plays vital roles in maintaining several important functions such as energy metabolism, immune response and cell signalling as well as the synthesis of Arg, NT, hexosamines and glycoproteins⁽ Reference Wu and Morris ^{114 ,} Reference Wang, Qiao and Yin ^{122 –} Reference Wu ^{125 )}. The amount of Gln obtained from milk is far from sufficient in newborns to support the Gln requirements for growth⁽ Reference Wu ^{126 )}. Different studies have all shown that Gln supplementation (0·3 g/kg per d) in formulas can increase the growth rate in LBW infants⁽ Reference Korkmaz, Yurdakok and Yigit ^{127 )}, improve the tolerance to enteral feeding and decrease morbidity during the 1st month⁽ Reference Neu, Roig and Meetze ^{128 –} Reference Vaughn, Thomas and Clark ^{130 )}. A previous study in IUGR piglets found that oral administration of Gln at 0·5 g/kg of body weight twice per d from days 0 to 21 of age could reduce amino acid oxidation, increase growth and reduce preweaning mortality⁽ Reference Wu, Bazer and Johnson ^{107 )}. Moreover, oral Gln (1 g/kg body weight every 12 h) during days 0 to 14 post weaning in LBW pigs induces an enhanced intestinal immunity by increasing heat shock protein 70 expression as well as the suppression of NF-κB⁽ Reference Zhong, Li and Huang ^{131 )}. Collectively, Gln is likely an effective amino acid to enhance the survival, immune response and postnatal growth of LBW infants.

Branched-chain amino acids

There are three amino acids recognised as BCAA: valine, isoleucine and leucine. They play vital parts in protein synthesis in skeletal muscle. The mechanisms that BCAA are involved in include the mTOR signalling pathway, decreasing rates of protein degradation⁽ Reference Davis, Fiorotto and Burrin ^{132 )} and regulating cell differentiation and apoptosis⁽ Reference Lei, Feng and Zhang ^{133 )}. Importantly, BCAA are substrates for the synthesis of glutamate and Arg in the metabolic pathway of amino acids⁽ Reference Rezaei, Wang and Wu ^{134 ,} Reference Yuan, Zhu and Shi ^{135 )}. A recent study using weaned LBW pigs as a model showed that dietary supplementation with 0·35 % l-leucine improved the growth rate of LBW piglets by increasing the levels of phosphorylated mTOR and ribosomal S6 kinase 1, and also by reducing muscle atrophy F-box protein⁽ Reference Xu, Bai and He ^{136 )}. Similar results have also been observed in fetal⁽ Reference Zheng, Huang and Cao ^{137 )} and postnatal LBW rats⁽ Reference Teodoro, Vianna and Torres-Leal ^{138 )}. Obviously, BCAA, particularly leucine, may have a potential effect on accelerating the early growth rate and protein synthesis in LBW offspring. Given the fact that BCAA play a major role in stimulating protein synthesis in skeletal muscle, the optimal BCAA supplement dosage should depend on whether it provides enough for maximum protein deposition in the skeletal muscle of LBW neonates.

l-Carnitine

l-Carnitine (3-hydroxy-4-N,N,N-trimethylaminobutyric acid) is a water-soluble quaternary amine essential for a series of indispensable functions in the intermediary metabolism of mammals. l-Carnitine serves as a shuttling molecule for the transportation of activated long-chain fatty acids from the cytosol into the mitochondrial matrix to produce energy⁽ Reference Keller, Ringseis and Priebe ^{139 )}. Preterm infants with LBW problems are at a high risk for carnitine deficiency because of an immature biosynthetic ability, insufficient transplacental transportation and exogenous supplementation⁽ Reference Whitfield, Smith and Sollohub ^{140 )}. A previous investigation implied that routine parenteral supplementation with l-carnitine had no demonstrable effect on growth, apnoea or length in LBW infants⁽ Reference Whitfield, Smith and Sollohub ^{140 )}. Nevertheless, evidence suggests that in piglets, adding l-carnitine to diets could accelerate the rates of protein and fat accretion⁽ Reference Keller, Ringseis and Priebe ^{139 ,} Reference Owen, Nelssen and Goodband ^{141 ,} Reference Owen, Nelssen and Goodband ^{142 )} by stimulating IGF-I signalling, while inhibiting the expression of pro-apoptotic and atrophy-related genes or genes of the ubiquitin–proteasome system⁽ Reference Keller, Ringseis and Priebe ^{139 ,} Reference Keller, Ringseis and Koc ^{143 )}. In particular, Losel et al.⁽ Reference Losel, Kalbe and Rehfeldt ^{144 )} reported that an oral administration of l-carnitine (400 mg/d) from 7 to 27 d of age resulted in an intensified myogenic proliferation in LBW suckling pigs, which demonstrated that increasing enteral l-carnitine could be considered as an effective method to improve growth outcomes of LBW neonates. Therefore, supplemental l-carnitine is recommended in LBW infants, but further clinical trials are needed to focus on the safe dosage and outcomes of l-carnitine usage.

PUFA

The major long-chain PUFA (LC-PUFA) such as arachidonic acid (ARA, 20 : 4n-6), EPA (20 : 5n-3) and DHA (22 : 6n-3) are essential nutrients for maintaining health, cognition and development during fetal as well as early postnatal life in humans⁽ Reference Isganaitis, Jimenez-Chillaron and Woo ^{22 ,} Reference Innis ^{145 )}. Previous evidence illustrated that neonates, including the LBW ones, can synthesise DHA and ARA from essential fatty acids such as linolenic acid (n-3 LC-PUFA) and linoleic acid (n-6 LC-PUFA)⁽ Reference Salem, Wegher and Mena ^{146 –} Reference Carnielli, Wattimena and Luijendijk ^{148 )}. However, the LC-PUFA synthesis rate in these LBW infants was not enough to meet the requirement for optimal growth and development⁽ Reference Salem, Wegher and Mena ^{146 ,} Reference Fleith and Clandinin ^{149 ,} Reference Uauy and Mena ^{150 )}. The decreased proportion of ARA to linoleic acid as well as DHA to α-linolenic acid was seen in the fetal plasma of IUGR pregnancies⁽ Reference Cetin, Giovannini and Alvino ^{151 )}, indicating a deficit in LC-PUFA profiles in the IUGR fetus. Therefore, dietary LC-PUFA supplementation can be considered as an efficient strategy to counteract the defective fatty acid composition of IUGR neonates. In a clinical trial, preterm infants fed with a formula containing DHA (0·16 %)+ARA (0·42 %) for the 1st year had higher lean body mass and reduced fat mass at 1 year of age⁽ Reference Groh-Wargo, Jacobs and Auestad ^{152 )}. A systematic review reported that ω-3 LC-PUFA supplementation was found to reduce the incidence of NEC in extremely preterm infants (≤32 weeks)⁽ Reference Zhang, Lavoie and Lacaze-Masmonteil ^{153 )}. Notably, supplementing fish oil (rich in EPA and DHA) has been considered as a potential nutritional intervention to facilitate catch-up growth with normal body composition in preterm infants⁽ Reference Yeung ^{154 )}, because of its effect on suppressing the differentiation of fat cells and fat accumulation⁽ Reference Azain ^{155 ,} Reference Ruzickova, Rossmeisl and Prazak ^{156 )}. In addition, EPA and DHA play a key part in mediating inflammatory response, which can in turn improve insulin sensitivity⁽ Reference Clifton and Nestel ^{157 ,} Reference Das ^{158 )}.

Nucleotides

NT are a group of bioactive agents regulating nearly all biochemical processes including transferring chemical energy, biosynthetic pathways and coenzyme components⁽ Reference Sauer, Mosenthin and Bauer ^{159 )}. NT account for approximately 20 % of the natural non-protein fractions in milk⁽ Reference Uauy ^{160 )} and play important roles in optimising intestinal and immunological function⁽ Reference Sauer, Eklund and Bauer ^{161 )}. De novo synthesis, salvage pathways and daily food are sources of NT in mammals⁽ Reference Che, Hu and Liu ^{162 )}. Cells of the intestinal mucosa have a limited capability for de novo synthesis⁽ Reference Savaiano and Clifford ^{163 )}. In a rapid growth stage, exogenous NT would become essential nutrients for optimal function especially when the mucosa has already been damaged, which is typically seen in LBW neonates. Recently, research using LBW pigs as a model showed that when LBW piglets received NT-supplemented formula from 7 to 28 d of age, intestinal villus height and lactase and maltase activity were improved, which led to a better growth rate⁽ Reference Che, Hu and Liu ^{162 )}.

Vitamins and minerals

The augmented intakes of Ca, P, trace elements and vitamins in LBW infants are significantly beneficial in improving postnatal growth outcomes. For instance, bone mineralisation is obviously higher in preterm infants when fed Ca- and P-enriched formulas⁽ Reference Lapillonne, Salle and Glorieux ^{164 )} compared with conventional preterm formulas. LBW formulas could be designed with much higher contents of Na and K in order to compensate for reduced kidney function⁽ Reference Hay and Hendrickson ^{68 ,} Reference Silverwood, Pierce and Hardy ^{165 )}. Because of a high incidence of vitamin A, D and E deficiency in VLBW infants⁽ Reference Kositamongkol, Suthutvoravut and Chongviriyaphan ^{166 ,} Reference Agarwal, Virmani and Jaipal ^{167 )}, addition of these vitamins is essential in parenteral or enteral feedings. Vitamin A supplementation in LBW neonates has the potential to improve lung and visual development⁽ Reference Mactier and Weaver ^{168 )} as well as to reduce death and retinopathy⁽ Reference Darlow and Graham ^{169 )}. Similarly, a systematic review showed that, as an antioxidant agent, vitamin E supplementation in preterm infants was able to reduce the risk for retinopathy and intracranial haemorrhage⁽ Reference Brion, Bell and Raghuveer ^{170 )}. The addition of vitamin D contributed to higher levels of serum vitamin D⁽ Reference Natarajan, Sankar and Agarwal ^{171 )}, higher Ca retention⁽ Reference Senterre, Putet and Salle ^{172 )}, and therefore lower incidence of bone hypomineralisation⁽ Reference Mathur, Saini and Mishra ^{173 )}. More clinical trials are still required to determine the optimal regimens for these nutrients.

Probiotics and prebiotics

Compared with adults, the enteric microbiota of infants is extremely unstable in terms of composition because of the fast development of the GIT⁽ Reference Palmer, Bik and DiGiulio ^{174 )}. Lactobacillus supplementation remarkably depresses feeding intolerance⁽ Reference Sari, Dizdar and Oguz ^{175 ,} Reference Oncel, Arayici and Sari ^{176 )} and increases growth velocity⁽ Reference Hartel, Pagel and Rupp ^{177 )} in VLBW infants. Supplementing single-strain Bifidobacterium in early life is able to improve body weight gain of LBW infants⁽ Reference Hartel, Pagel and Rupp ^{177 ,} Reference Yamasaki, Totsu and Uchiyama ^{178 )} and promote Bifidobacterium colonisation⁽ Reference Li, Shimizu and Hosaka ^{179 )}. Furthermore, a meta-analysis of twenty randomised and controlled trials showed reduced risks for NEC and mortality were achieved by Bifidobacterium or Lactobacillus supplementation in preterm VLBW infants⁽ Reference Wang, Dong and Zhu ^{180 )}. Accordingly, the use of nutritional intervention to foster a beneficial intestinal microbiota composition can be a good strategy to prevent potential health problems⁽ Reference Marques, Wall and Ross ^{181 )}. Multi-strain probiotic combinations have shown greater efficacy than single-strain probiotic supplementation for GIT and immune outcomes in animals and humans⁽ Reference Chapman, Gibson and Rowland ^{182 )}. A combination of Bifidobacterium and Lactobacillus supplementation is proven to reduce the occurrence of NEC⁽ Reference Braga, da Silva and de Lira ^{183 ,} Reference Saengtawesin, Tangpolkaiwalsak and Kanjanapattankul ^{184 )}, mortality⁽ Reference Lin, Hsu and Chen ^{185 )} and to increase the growth rate⁽ Reference Al-Hosni, Duenas and Hawk ^{186 )} in LBW infants.

Supplementation with prebiotics in formulas could promote the growth of beneficial microbes in LBW infants. Generally, prebiotics consist of one or more carbohydrates such as inulin, lactulose, fructo-oligosaccharides (FOS) or galacto-oligosaccharides (GOS). For example, supplementing the preterm formula with a mixture of FOS and GOS may stimulate the growth of Bifidobacteria ⁽ Reference Boehm, Lidestri and Casetta ^{187 ,} Reference Westerbeek, van Elburg and van den Berg ^{188 )}, whereas lactulose addition increases the growth of Lactobacillus ⁽ Reference Riskin, Hochwald and Bader ^{189 )}. Moreover, Dilli et al.⁽ Reference Dilli, Aydin and Fettah ^{190 )} reported that adding a synbiotic (Bifidobacterium lactis plus inulin) to breastmilk or formula could decrease the risk for NEC in VLBW infants. Similar results were observed by supplementing another kind of synbiotic containing Lactobacillus, Bifidobacterium and FOS⁽ Reference Nandhini, Biswal and Adhisivam ^{191 )}. Overall, we can speculate that supplementing probiotics and prebiotics alone, or as a combination, might be useful for optimising the intestinal micro-ecology, GIT health and further stimulating the growth outcomes of LBW offspring.

Hormone regulation