Hostname: page-component-78c5997874-ndw9j Total loading time: 0 Render date: 2024-10-30T09:02:55.209Z Has data issue: false hasContentIssue false

Nutritional support for low birth weight infants: insights from animal studies

Published online by Cambridge University Press:  13 June 2017

Na Li
Affiliation:
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People’s Republic of China Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, People’s Republic of China
Wei Wang
Affiliation:
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People’s Republic of China Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, People’s Republic of China
Guoyao Wu
Affiliation:
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People’s Republic of China Department of Animal Science, Texas A&M University, College Station, TX 77843-2471, USA
Junjun Wang*
Affiliation:
State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, People’s Republic of China Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, Beijing 100193, People’s Republic of China
*
*Corresponding author: J. Wang, fax +86 10 6273 3688, email jkywjj@hotmail.com
Rights & Permissions [Opens in a new window]

Abstract

Infants born with low birth weights (<2500 g, LBW), accounting for about 15 % of newborns, have a high risk for postnatal growth failure and developing the metabolic syndromes such as type 2 diabetes, CVD and obesity later in life. Improper nutrition provision during critical stages, such as undernutrition during the fetal period or overnutrition during the neonatal period, has been an important mediator of these metabolic diseases. Considering the specific physiological status of LBW infants, nutritional intervention and optimisation during early life merit further attention. In this review, the physiological and metabolic defects of LBW infants were summarised from a nutritional perspective. Available strategies for nutritional interventions and optimisation of LBW infants, including patterns of nutrition supply, macronutrient proportion, supplementation of amino acids and their derivatives, fatty acids, nucleotides, vitamins, minerals as well as hormone and microbiota manipulators, were reviewed with an aim to provide new insights into the advancements of formulas and human-milk fortifiers.

Type
Full Papers
Copyright
Copyright © The Authors 2017 

According to the WHO, infants with a birth weight <2500 g, irrespective of gestation, are defined as low birth weight (LBW)( Reference Jain and Singhal 1 ). Infants with LBW have high morbidity and mortality during the neonatal period as an outcome of intra-uterine growth restriction (IUGR) or preterm birth( Reference Lawn, Kerber and Enweronu-Laryea 2 ). Although great efforts have been put into nutritional management and clinical support for pregnant women, LBW infants still account for about 15 % of newborns( 3 ). Among all of the environmental factors leading to the occurrence of IUGR, maternal undernutrition has been recognised as the most important. Because of improper nutritional provision during the fetal period, a critical period according to the nutritional programming theory, LBW infants not only show growth failure during the neonatal period, but also lifelong metabolic disturbance( Reference Garite, Clark and Thorp 4 Reference Claris, Beltrand and Levy-Marchal 6 ). Therefore, nutritional intervention of LBW infants during their neonatal stage has aroused great attention in recent years. Because of the ethical issues involved, animal models have been widely used to investigate the physiological differences between LBW offspring and normal ones as well as the nutritional support strategies( Reference Dinerstein, Nieto and Solana 7 ).

In this review, we will focus on discussing the physiological differences related to provision and digestion of nutrients between LBW infants and normal infants. Furthermore, we provide information about the current nutritional support given to these LBW infants, with a focus on the neonatal stage.

Consequences of being born with low birth weights

Catch-up growth and risks for the metabolic syndromes

The occurrence of IUGR reflects that the infant probably experienced undernutrition during its development within the uterus. In this case, as a protective mechanism, the fetus prefers to allocate the limited nutrients to vital organs (e.g. the brain) for survival and development, at the expense of somatic growth. Therefore, the growth-hormone system is down-regulated, as indicated by the lower serum concentrations of insulin, insulin-like growth factor (IGF) and insulin-like growth factor-binding protein 3 (IGFBP-3)( Reference Giudice, Dezegher and Gargosky 8 Reference Kajantie, Dunkel and Rutanen 10 ). By using IUGR piglets as a model, Wang et al. ( Reference Wang, Zhang and Zhou 11 ) reported that IUGR piglets showed lower concentrations of insulin and IGF-I in the jejunal mucosa when compared with normal littermates. IGF and IGFBP-3 reflect the growth velocity in childhood, and several studies have reported that these two factors can be used as predictors of catch-up growth of LBW infants during the neonatal period( Reference Thieriot-Prevost, Boccara and Francoual 12 Reference Leger, Noel and Limal 14 ).

Normally, catch-up growth in LBW infants is achieved by overnutrition compensation, and it is postulated to erase the growth deficit generated during the fetal period( Reference Jain and Singhal 1 ). However, given the fact that IUGR infants are born with lower concentrations of insulin, IGF-I and IGFBP-3, the sudden shift to a normal or overly compensatory diet after birth might increase these parameters during the first 3 months of life( Reference Leger, Noel and Limal 14 , Reference Cianfarani, Germani and Rossi 15 ), which will lead to insulin resistance in tissues to prevent hypoglycaemia( Reference Jain and Singhal 1 , Reference Cianfarani, Germani and Branca 16 ). Therefore, catch-up growth actually reflects an insulin-resistance state( Reference Dulloo, Jacquet and Seydoux 17 ). Meanwhile, preferential abdominal fat deposition, excess circulating lipids and ectopic fat storage were observed in the catch-up growth infants, all of which have been implicated in the risk for developing obesity, type II diabetes (T2D), hypertension and CVD( Reference Barker, Osmond and Forsen 18 , Reference Dulloo 19 ). Studies with rodents showed that an accelerated postnatal growth induced excessive adiposity, increased adipocyte sizes and glucose intolerance( Reference Crescenzo, Samec and Antic 20 Reference Wang, Tang and Wang 23 ). Notably, some researchers stated that growth in different neonatal periods may have different effects on later T2D and CVD risks. It has been reported that catch-up growth that occurred during early infancy (the first 3 months) has a greater programming effect on adiposity and metabolism when compared with growth in later stages of infancy( Reference Jain and Singhal 1 ).

Furthermore, previous studies have suggested that small-at-birth people have higher fasting plasma cortisol concentrations in their adult lives and increased adrenal responsivity to adrenocorticotropic hormone stimulation, which can then reduce lean body mass and increase lipid accumulation( Reference Phillips, Barker and Fall 24 Reference Phillips, Walker and Reynolds 27 ). As a consequence, the elevated cortisol levels may present a possible link between LBW and adult metabolic syndrome. During the neonatal period, cortisol might also play a role in limiting IGFBP-3 proteolysis and therefore reducing IGF bioavailability( Reference Cianfarani, Geremia and Scott 28 ) and leading to growth failure in LBW children.

Digestive function deficiency

Recently, by using different experimental models, it has been reported that LBW offspring such as LBW fetuses, neonates, children or young adults have a higher incidence of short- and long-term dysfunctions in several vital organs, as indicated in Table 1. For example, evidence has shown abnormal brain volumes( Reference Bjuland, Rimol and Lohaugen 29 ) and muscle fibre distributions( Reference Jensen, Storgaard and Madsbad 40 ) of young LBW adults, lower bone quality of preterm children( Reference Longhi, Mercolini and Carloni 41 ) as well as smaller thymic size of IUGR human fetuses( Reference Cromi, Ghezzi and Raffaelli 42 ). Besides lower tissue weight, dysregulated expressions of proteins were observed in the liver, skeletal muscle and small intestine of newborn IUGR pigs( Reference Wang, Chen and Li 31 ).

Table 1 Examples of epidemiological and animal studies that reveal alterations in vital organs of low birth weight (LBW) offspring compared with normal ones

VLBW, very low birth weight, <1500 g; IUGR, intra-uterine growth restriction; SGA, small for gestational age.

Among these organs, the gastrointestinal tract (GIT) is of paramount importance in postnatal nutrient acquisition. The epithelial barrier of the GIT is involved in the first steps of postnatal immune system maturation, providing protection against food antigens and invasion of environmental micro-organisms( Reference Xu, Mellor and Birtles 33 , Reference D’Inca, Gras-Le Guen and Che 45 ). Most studies on the effect of LBW on GIT health were carried out in animal models, especially on piglets. LBW piglets normally show impaired gastrointestinal development, which further imposes limitations on postnatal body growth and development of other organs( Reference Xu, Mellor and Birtles 33 ). Compared with normal-birth weight (NBW) newborns, LBW piglets show a reduced small intestinal weight and a reduced small intestine:body weight ratio up to 21 d of age( Reference Wang, Chen and Li 46 ). The reduced ratio of intestinal weight:length in these LBW piglets indicates a thinner intestinal wall( Reference Wang, Lin and Liu 32 , Reference Wang, Wu and Lin 47 ). Differences in intestinal architecture between IUGR and NBW neonates were widely documented, indicating that the intestinal absorptive surface was smaller in IUGR piglets during the early days of life, as evidenced by the reduced ratio of intestinal villus height:crypt depth( Reference Xu, Mellor and Birtles 33 , Reference He, Ren and Kong 34 , Reference D’Inca, Gras-Le Guen and Che 45 , Reference Wang, Huo and Shi 48 Reference D’Inca, Kloareg and Gras-Le Guen 50 ). This reduction of exchange surface is crucial because of its role in processing dietary nutrients into available molecules and regulating the flux of antigenic material( Reference D’Inca, Kloareg and Gras-Le Guen 50 ). Further proteome analysis of the jejunum of LBW piglets revealed that the expression of key proteins involved in major biological processes such as absorption, digestion and transport of nutrients, cell apoptosis, nutrient metabolism, cellular redox homoeostasis and stress response were affected by birth weight during the first 21 d of life( Reference Wang, Chen and Li 46 , Reference Wang, Wu and Lin 47 , Reference D’Inca, Kloareg and Gras-Le Guen 50 ). Moreover, He et al.( Reference He, Ren and Kong 34 ) have reported that IUGR piglets have a distinct metabolic status compared with NBW piglets at 21 d of age, with changes related to lipogenesis, lipid oxidation, energy supply and utilisation, amino acid and protein metabolism, and antioxidant ability.

Gut bacterial colonisation of LBW piglets is also altered during the early days of life( Reference D’Inca, Gras-Le Guen and Che 45 ). For example, preterm LBW infants had reduced population levels of strict anaerobes such as Bifidobacterium and Bacteroides, and had a high prevalence of Staphylococcus, Enterobacteriaceae, Enterococcaceae and other lactic acid bacteria including the genus Lactobacillus in a low-diversity bacterial ecosystem( Reference Jacquot, Neveu and Aujoulat 51 Reference Arboleya, Solis and Fernandez 53 ). In summary, these results all suggest that LBW newborns are associated with both immediate and long-term altered intestinal adaptation during the neonatal period.

Possible nutritional interventions for improving growth and health of low birth weight infants

Appropriate patterns of nutrient delivery

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.

Macronutrients

LBW infants are generally fed high-protein/energy formulas to improve their growth rates and N retention( Reference Kashyap, Schulze and Forsyth 77 Reference Thureen and Heird 81 ). For instance, Fenton et al. ( Reference Fenton, Premji and Al-Wassia 82 ) demonstrated that a higher protein intake (≥3·0 but <4·0 g/kg BW per d) could accelerate weight gain and N accretion in formula-fed hospitalised infants, which indicated by an enhancement of postnatal growth. Providing a nutrient-rich formula to preterm infants (20 % energy-enriched and 40–60 % more protein and minerals than term formula) increased body weight, length and head circumference growth during the first 18 months( Reference Young, Morgan and McCormick 83 ). Similar results were shown in a piglet study in which the LBW piglets had a comparable growth rate with the normal piglets when fed a high-protein content diet between 7 and 28 d of life( Reference Morise, Seve and Mace 84 ). Han( Reference Han 85 ) also reported that when LBW piglets received a high-nutrition-level diet with all nutrients at about 1·5-fold those of the control, they had markedly increased weight gain of the psoas major muscle. This was probably due to the enhanced gene expressions of IGF-I, IGF-I receptor and mammalian target of rapamycin (mTOR).

Another widely used strategy to promote the growth of LBW infants is increasing energy intake. However, it has been stated that the major effect of higher energy intake (594 v. 502 kJ/d (142 v. 120 kcal/d)) in LBW infants is an increase in fat accretion( Reference Kashyap, Schulze and Forsyth 77 ). Studies in experimental animals show that protein/energy malnutrition can affect the utilisation and deposition of protein and fat( Reference Weinkove, Weinkove and Pimstone 86 ). High nutrient intake in IUGR piglets led to abnormal immune function during the suckling period by lowering serum concentrations of cytokines such as TNF and IL-1β. Moreover, intense nutrient intake induces excessive oxidative stress( Reference Feillet-Coudray, Sutra and Fouret 87 Reference Devaraj, Wang-Polagruto and Polagruto 89 ), which can impose a further burden on the immature antioxidant system in LBW offspring( Reference Hracsko, Orvos and Novak 90 Reference Wang, Degroote and Van Ginneken 92 ).

Considering the potential risk for inducing metabolic problems, the intensive nutrition strategy might not be a proper nutritional intervention for LBW infants. Research on rats showed that postnatal energy restriction can be considered as an effective strategy to alleviate the metabolic syndromes in LBW offspring, like obesity and diabetes( Reference Desai, Gayle and Babu 93 Reference Garg, Thamotharan and Dai 95 ). Che et al. ( Reference Che, Xuan and Hu 96 ) reported that restricting the intake of 7-d-old IUGR piglets (approximately 70 % of the control’s intake) can improve the antioxidant system at the expense of maintaining a low growth rate in the neonatal phase( Reference Hu, Liu and Yan 97 ).

It is worth noting that protein:energy ratio (PER) of diets will be important for the relative composition of net protein and fat stored in tissues while considering the different nutritional requirements of growth and maintenance( Reference Hay, Brown and Denne 98 ). In this case, therefore, an appropriate PER in infant formulas is necessary to maintain a positive N balance, ensure protein utilisation and prevent excessive fat storage( Reference Prince and Groh-Wargo 57 , Reference Kashyap 99 ). The PER of mature human milk ranges from 1·3–1·8 g/418 kJ (100 kcal), whereas the ratio ranges from 2·2–2·5 g/418 kJ (100 kcal) in standard formulas for normal infants( Reference Raiha, Fazzolari-Nesci and Cajozzo 100 ). However, a higher PER, approximately 3 g/418 kJ (100 kcal), is recommended for preterm LBW infants( Reference Prince and Groh-Wargo 57 , Reference Su 101 ), which would lead to increased lean mass with relatively decreased fat deposition( Reference Kashyap 99 ). Once protein intake is adequate to meet the needs of lean body accretion, excessive energy will primarily lead to relatively more fat deposition( Reference Hay, Brown and Denne 98 ), and then increase the risk for adult obesity( Reference Belfort, Gillman and Buka 102 ). Taken together, the optimal constitution and appropriate PER levels in formulas designed specifically for these LBW infants can be useful in achieving the desired growth rate while avoiding extra stress on their defective metabolic system.

Functional components applied to optimise nutritional support for low birth weights infants

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

Leptin

Leptin is a 16-kDa cytokine mainly produced by the adipose tissue and is responsible for the central regulation of food intake and energy balance as well as for enhancing the postnatal maturation of numerous peripheral organs. Its deficiency will lead to morbid obesity and diabetes as well as various neuroendocrine anomalies( Reference Gautron and Elmquist 192 Reference Attig, Djiane and Gertler 194 ). Evidence illustrates that human newborns with LBW show significantly lower serum leptin levels than do normal newborns( Reference Jaquet, Leger and Levy-Marchal 195 ). Studies using pigs as a model confirmed that this reduction may be a result of abnormal hypothalamic distribution of leptin receptors( Reference Attig, Djiane and Gertler 194 ) and lower expressions of the leptin gene in perineal adipose tissue( Reference Morise, Seve and Mace 196 ). In piglets, leptin injection (0·5 mg/kg) from days 2 to 10 of age can improve body weight and lean mass of LBW piglets by increasing organ weights, like that of the pancreas, liver and lung( Reference Attig, Djiane and Gertler 194 ). Interestingly, leptin treatment can normalise the composition of the adipose tissue by decreasing white-adipocyte density while increasing the individual adipocyte size( Reference Attig, Djiane and Gertler 194 ). These findings suggest that leptin treatment in early postnatal life has the potential to correct abnormal fat deposition in LBW offspring through regulation of body weight gain, organ development and body composition.

Insulin and insulin-like growth factor-I

In neonatal miniature pigs, oral insulin administration can stimulate ileal growth and enhance the specific activities of lactase and maltase( Reference Shulman 197 ). Several studies demonstrated that an extra addition of IGF-I in infant formula might improve GIT growth and function in newborn colostrum-deprived pigs( Reference Xu, Mellor and Birtles 198 Reference Burrin, Wester and Davis 200 ). Infusion of IGF-1 (4 μg/h) to IUGR piglets aged 3–10 d evidently increased the circulating concentration of IGF-I and the rate of weight gain by approximately 10 %, because of the increase in protein and fat accretion levels( Reference Schoknecht, Ebner and Skottner 201 ). The potential mechanisms of this enhancement contain a stimulated cell proliferation in the GIT( Reference Xu, Mellor and Birtles 198 ), increased brush-border disaccharidase activity( Reference Houle, Schroeder and Odle 199 ) and increased intestinal weight and ileal villus height( Reference Burrin, Wester and Davis 200 ). In VLBW infants, continuous insulin infusion (0·05 units/kg per h) from 24 h after birth to 7 d of age led to an increase in IGF-I concentrations in the serum at 28 d and therefore, an increase in both body weight and head circumference( Reference Habbout, Li and Rochette 21 ). Similar insulin therapy (0·025 units/kg per h) reduced the incidence of hyperglycaemia in VLBW infants( Reference Beardsall, Ogilvy-Stuart and Frystyk 202 ). On the basis of this information, IGF-I and insulin could be two potential growth promoters in LBW offspring during the early postnatal period.

Conclusions and perspectives

In addition to the reduced growth rate after birth, LBW infants are also born with abnormalities in hormone regulation and nutrient utilisation, all of which might have adverse effects on lifelong health. Considering the physiological defects of LBW infants, nutritional interventions during the neonatal stage should focus on promoting the postnatal growth rate without causing potential metabolic problems. Available nutrition strategies based on the preceding information have been summarised in Table 2. First, the best pattern of nutrition supply is transitioning from a combination of PN and EN to full enteral feeding during the early life of LBW infants. The benefits and shortcomings of continuous v. intermittent bolus feeding needs further consideration. Next, the optimal protein and energy contents in the formulas for LBW infants, based on an appropriate PER, should be adopted for preventing metabolic problems caused by high protein or energy levels. Specifically, some functional components (see Table 2), such as functional amino acids and its derivatives, LC-PUFA, NT, vitamins and minerals, probiotics and prebiotics as well as hormonal manipulators could be used as additives in the formulas and HMF. They could also be used as parenteral nutrients to compensate for congenital physiological defects and improve postnatal outcomes in LBW infants. We believe that a combination of these functional components will contribute to an extra-positive effect on LBW neonates’ health and growth. More research is also needed to better understand the molecular and cellular mechanisms by which the mentioned nutrients regulate the short- and long-term growth of LBW infants. Another suggestion for further studies would be identifying the differences in metabolism and nutritional requirements between preterm and term LBW infants, and then designing the corresponding HMF and formulas for these two types of neonates. In addition, when the use of LBW infants is limited, a piglet model would be more suitable for the investigation of clinical nutrition because of high similarity in terms of anatomy, genetics and physiology( Reference Fritz, Desai and Shah 203 , Reference Meurens, Summerfield and Nauwynck 204 ), compared with rodent models.

Table 2 Examples of nutrition strategies for improving growth, development and health of low birth weight (LBW) infants

PN, parenteral nutrition; EN, enteral nutrition; HMF, human-milk fortifiers; IUGR: intra-uterine growth restriction; PER, protein:energy ratio; Arg, arginine; GIT, gastrointestinal tract; Gln, glutamine; LC-PUFA, long-chain PUFA; ARA, arachidonic acid; NT, nucleotides; VLBW, very low birth weight, <1500 g; NEC, necrotising enterocolitis; FOS, fructo-oligosaccharides; GOS, galacto-oligosaccharides; ; IGF-I, insulin-like growth factor.

Acknowledgements

The authors thank Mr Daniel Long and Dr Ying Wang for assistance in manuscript preparation.

This work was supported by the National Natural Science Foundation of China (nos 31272449, 31422052, 31572412 and 31630074), the National Key Research and Development Program of China (2016YFD0500506), the ‘111’ Project (B16044), Jinxinnong University Animal Science Developmental Foundation, Hunan Co-Innovation Center of Animal Production Safety (CICAPS) and Agriculture and Food Research Initiative Competitive Grants (2014-67015-21770, 2015-67015-23276 and 2016-67015-24958) from the United States Department of Agriculture (USDA) National Institute of Food and Agriculture, and Texas A&M AgriLife Research (H-8200).

The authors’ contributions are as follows: J. W. designed the framework of the draft. N. L. and W. W. collected the literature and drafted the manuscript. J. W., G. W. and W. W. revised and finalised the draft.

The authors declare that there are no conflicts of interest.

References

1. Jain, V & Singhal, A (2012) Catch up growth in low birth weight infants: striking a healthy balance. Rev Endocr Metab Disord 13, 141147.CrossRefGoogle ScholarPubMed
2. Lawn, JE, Kerber, K, Enweronu-Laryea, C, et al. (2010) 3.6 million neonatal deaths – what is progressing and what is not? Semin Perinatol 34, 371386.CrossRefGoogle ScholarPubMed
3. World Health Organization (2011) Guidelines on Optimal Feeding of Low Birth-Weight Infants in Low- and Middle-Income Countries. WHO Guidelines Approved by the Guidelines Review Committee. Geneva: WHO.Google Scholar
4. Garite, TJ, Clark, R & Thorp, JA (2004) Intrauterine growth restriction increases morbidity and mortality among premature neonates. Am J Obstet Gynecol 191, 481487.Google Scholar
5. Berends, LM, Fernandez-Twinn, DS, Martin-Gronert, MS, et al. (2013) Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue. Int J Obes (Lond) 37, 10511057.Google Scholar
6. Claris, O, Beltrand, J & Levy-Marchal, C (2010) Consequences of intrauterine growth and early neonatal catch-up growth. Semin Perinatol 34, 207210.CrossRefGoogle ScholarPubMed
7. Dinerstein, A, Nieto, RM, Solana, CL, et al. (2006) Early and aggressive nutritional strategy (parenteral and enteral) decreases postnatal growth failure in very low birth weight infants. J Perinatol 26, 436442.CrossRefGoogle ScholarPubMed
8. Giudice, LC, Dezegher, F, Gargosky, SE, et al. (1995) Insulin-like growth-factors and their binding-proteins in the term and preterm human fetus and neonate with normal and extremes of intrauterine growth. J Clin Endocrinol Metab 80, 15481555.Google Scholar
9. Lassarre, C, Hardouin, S, Daffos, F, et al. (1991) Serum insulin-like growth factors and insulin-like growth factor binding proteins in the human fetus. Relationships with growth in normal subjects and in subjects with intrauterine growth retardation. Pediatr Res 29, 219225.Google Scholar
10. Kajantie, E, Dunkel, L, Rutanen, EM, et al. (2002) IGF-I, IGF binding protein (IGFBP)-3, phosphoisoforms of IGFBP-1, and postnatal growth in very low birth weight infants. J Clin Endocrinol Metab 87, 21712179.Google Scholar
11. Wang, YX, Zhang, LL, Zhou, GL, et al. (2012) Dietary L-arginine supplementation improves the intestinal development through increasing mucosal Akt and mammalian target of rapamycin signals in intra-uterine growth retarded piglets. Br J Nutr 108, 13711381.Google Scholar
12. Thieriot-Prevost, G, Boccara, JF, Francoual, C, et al. (1988) Serum insulin-like growth factor 1 and serum growth-promoting activity during the first postnatal year in infants with intrauterine growth retardation. Pediatr Res 24, 380383.CrossRefGoogle ScholarPubMed
13. Ozkan, H, Aydin, A, Demir, N, et al. (1999) Associations of IGF-I, IGFBP-1 and IGFBP-3 on intrauterine growth and early catch-up growth. Biol Neonate 76, 274282.CrossRefGoogle ScholarPubMed
14. Leger, J, Noel, M, Limal, JM, et al. (1996) Growth factors and intrauterine growth retardation. II. Serum growth hormone, insulin-like growth factor (IGF) I, and IGF-binding protein 3 levels in children with intrauterine growth retardation compared with normal control subjects: prospective study from birth to two years of age. Study Group of IUGR. Pediatr Res 40, 101107.CrossRefGoogle Scholar
15. Cianfarani, S, Germani, D, Rossi, P, et al. (1998) Intrauterine growth retardation: evidence for the activation of the insulin-like growth factor (IGF)-related growth-promoting machinery and the presence of a cation-independent IGF binding protein-3 proteolytic activity by two months of life. Pediatr Res 44, 374380.Google Scholar
16. Cianfarani, S, Germani, D & Branca, F (1999) Low birthweight and adult insulin resistance: the ‘catch-up growth’ hypothesis. Arch Dis Child Fetal Neonatal Ed 81, F71F73.Google Scholar
17. Dulloo, AG, Jacquet, J, Seydoux, J, et al. (2006) The thrifty ‘catch-up fat’ phenotype: its impact on insulin sensitivity during growth trajectories to obesity and metabolic syndrome. Int J Obes (Lond) 30, Suppl. 4, S23S35.CrossRefGoogle ScholarPubMed
18. Barker, DJP, Osmond, C, Forsen, TJ, et al. (2005) Trajectories of growth among children who have coronary events as adults. N Engl J Med 353, 18021809.Google Scholar
19. Dulloo, AG (2006) Regulation of fat storage via suppressed thermogenesis: a thrifty phenotype that predisposes individuals with catch-up growth to insulin resistance and obesity. Horm Res 65, Suppl. 3, 9097.Google Scholar
20. Crescenzo, R, Samec, S, Antic, V, et al. (2003) A role for suppressed thermogenesis favoring catch-up fat in the pathophysiology of catch-up growth. Diabetes 52, 10901097.Google Scholar
21. Habbout, A, Li, N, Rochette, L, et al. (2013) Postnatal overfeeding in rodents by litter size reduction induces major short- and long-term pathophysiological consequences. J Nutr 143, 553562.Google Scholar
22. Isganaitis, E, Jimenez-Chillaron, J, Woo, M, et al. (2009) Accelerated postnatal growth increases lipogenic gene expression and adipocyte size in low-birth weight mice. Diabetes 58, 11921200.Google Scholar
23. Wang, J, Tang, H, Wang, X, et al. (2016) The structural alteration of gut microbiota in low-birth-weight mice undergoing accelerated postnatal growth. Sci Rep 6, 27780.Google Scholar
24. Phillips, DI, Barker, DJ, Fall, CH, et al. (1998) Elevated plasma cortisol concentrations: a link between low birth weight and the insulin resistance syndrome? J Clin Endocrinol Metab 83, 757760.Google Scholar
25. Ward, AM, Syddall, HE, Wood, PJ, et al. (2004) Fetal programming of the hypothalamic-pituitary-adrenal (HPA) axis: low birth weight and central HPA regulation. J Clin Endocrinol Metab 89, 12271233.Google Scholar
26. Reynolds, RM, Walker, BR, Syddall, HE, et al. (2001) Altered control of cortisol secretion in adult men with low birth weight and cardiovascular risk factors. J Clin Endocrinol Metab 86, 245250.Google Scholar
27. Phillips, DI, Walker, BR, Reynolds, RM, et al. (2000) Low birth weight predicts elevated plasma cortisol concentrations in adults from 3 populations. Hypertension 35, 13011306.Google Scholar
28. Cianfarani, S, Geremia, C, Scott, CD, et al. (2002) Growth, IGF system, and cortisol in children with intrauterine growth retardation: is catch-up growth affected by reprogramming of the hypothalamic-pituitary-adrenal axis? Pediatr Res 51, 9499.Google Scholar
29. Bjuland, KJ, Rimol, LM, Lohaugen, GC, et al. (2014) Brain volumes and cognitive function in very-low-birth-weight (VLBW) young adults. Eur J Paediatr Neurol 18, 578590.Google Scholar
30. Liu, C, Lin, G, Wang, X, et al. (2013) Intrauterine growth restriction alters the hepatic proteome in fetal pigs. J Nutr Biochem 24, 954959.Google Scholar
31. Wang, J, Chen, L, Li, D, et al. (2008) Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. J Nutr 138, 6066.Google Scholar
32. Wang, X, Lin, G, Liu, C, et al. (2014) Temporal proteomic analysis reveals defects in small-intestinal development of porcine fetuses with intrauterine growth restriction. J Nutr Biochem 25, 785795.Google Scholar
33. Xu, RJ, Mellor, DJ, Birtles, MJ, et al. (1994) Impact of intrauterine growth retardation on the gastrointestinal tract and the pancreas in newborn pigs. J Pediatr Gastroenterol Nutr 18, 231240.Google Scholar
34. He, Q, Ren, P, Kong, X, et al. (2011) Intrauterine growth restriction alters the metabonome of the serum and jejunum in piglets. Mol Biosyst 7, 21472155.CrossRefGoogle ScholarPubMed
35. Shen, Q, Xu, H, Wei, LM, et al. (2010) A comparative proteomic study of nephrogenesis in intrauterine growth restriction. Pediatr Nephrol 25, 10631072.Google Scholar
36. Gheissari, A, Naseri, F, Pourseirafi, H, et al. (2012) Postnatal kidney function in children born very low birth weight. Iran J Kidney Dis 6, 256261.Google Scholar
37. Wang, T, Liu, C, Feng, C, et al. (2013) IUGR alters muscle fiber development and proteome in fetal pigs. Front Biosci 18, 598607.Google Scholar
38. Bauer, R, Gedrange, T, Bauer, K, et al. (2006) Intrauterine growth restriction induces increased capillary density and accelerated type I fiber maturation in newborn pig skeletal muscles. J Perinat Med 34, 235242.CrossRefGoogle ScholarPubMed
39. Beauchamp, B, Ghosh, S, Dysart, MW, et al. (2015) Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice. Int J Obesity 39, 702711.CrossRefGoogle ScholarPubMed
40. Jensen, CB, Storgaard, H, Madsbad, S, et al. (2007) Altered skeletal muscle fiber composition and size precede whole-body insulin resistance in young men with low birth weight. J Clin Endocrinol Metab 92, 15301534.Google Scholar
41. Longhi, S, Mercolini, F, Carloni, L, et al. (2015) Prematurity and low birth weight lead to altered bone geometry, strength, and quality in children. J Endocrinol Invest 38, 563568.Google Scholar
42. Cromi, A, Ghezzi, F, Raffaelli, R, et al. (2009) Ultrasonographic measurement of thymus size in IUGR fetuses: a marker of the fetal immunoendocrine response to malnutrition. Ultrasound Obstet Gynecol 33, 421426.Google Scholar
43. Lin, Y, Wang, JJ, Wang, XQ, et al. (2013) T cells development is different between thymus from normal and intrauterine growth restricted pig fetus at different gestational stage. Asian-Australas J Anim Sci 26, 343348.Google Scholar
44. Contreras, YM, Yu, X, Hale, MA, et al. (2011) Intrauterine growth restriction alters T-lymphocyte cell number and dual specificity phosphatase 1 levels in the thymus of newborn and juvenile rats. Pediatr Res 70, 123129.Google Scholar
45. D’Inca, R, Gras-Le Guen, C, Che, L, et al. (2011) Intrauterine growth restriction delays feeding-induced gut adaptation in term newborn pigs. Neonatology 99, 208216.Google Scholar
46. Wang, JJ, Chen, LX, Li, DF, et al. (2008) Intrauterine growth restriction affects the proteomes of the small intestine, liver, and skeletal muscle in newborn pigs. J Nutr 138, 6066.Google Scholar
47. Wang, XQ, Wu, WZ, Lin, G, et al. (2010) Temporal proteomic analysis reveals continuous impairment of intestinal development in neonatal piglets with intrauterine growth restriction. J Proteome Res 9, 924935.Google Scholar
48. Wang, T, Huo, YJ, Shi, F, et al. (2005) Effects of intrauterine growth retardation on development of the gastrointestinal tract in neonatal pigs. Biol Neonate 88, 6672.Google Scholar
49. Wiyaporn, M, Thongsong, B & Kalandakanond-Thongsong, S (2013) Growth and small intestine histomorphology of low and normal birth weight piglets during the early suckling period. Livest Sci 158, 215222.Google Scholar
50. D’Inca, R, Kloareg, M, Gras-Le Guen, C, et al. (2010) Intrauterine growth restriction modifies the developmental pattern of intestinal structure, transcriptomic profile, and bacterial colonization in neonatal pigs. J Nutr 140, 925931.Google Scholar
51. Jacquot, A, Neveu, D, Aujoulat, F, et al. (2011) Dynamics and clinical evolution of bacterial gut microflora in extremely premature patients. J Pediatr 158, 390396.Google Scholar
52. Arboleya, S, Binetti, A, Salazar, N, et al. (2012) Establishment and development of intestinal microbiota in preterm neonates. FEMS Microbiol Ecol 79, 763772.Google Scholar
53. Arboleya, S, Solis, G, Fernandez, N, et al. (2012) Facultative to strict anaerobes ratio in the preterm infant microbiota: a target for intervention? Gut Microbes 3, 583588.Google Scholar
54. Fanaro, S (2013) Feeding intolerance in the preterm infant. Early Hum Dev 89, Suppl. 2, S13S20.Google Scholar
55. Ziegler, EE, Thureen, PJ & Carlson, SJ (2002) Aggressive nutrition of the very low birthweight infant. Clin Perinatol 29, 225244.Google Scholar
56. Heird, WC (2001) Determination of nutritional requirements in preterm infants, with special reference to ‘catch-up’ growth. Semin Neonatol 6, 365375.Google Scholar
57. Prince, A & Groh-Wargo, S (2013) Nutrition management for the promotion of growth in very low birth weight premature infants. Nutr Clin Pract 28, 659668.Google Scholar
58. Valentine, CJ, Fernandez, S, Rogers, LK, et al. (2009) Early amino-acid administration improves preterm infant weight. J Perinatol 29, 428432.Google Scholar
59. Patel, P & Bhatia, J (2017) Total parenteral nutrition for the very low birth weight infant. Semin Fetal Neonatal Med 22, 27.Google Scholar
60. Moyses, H, Johnson, M, Leaf, A, et al. (2013) Early parenteral nutrition and growth outcomes in preterm infants: a systematic review and meta-analysis. Am J Clin Nutr 97, 816826.Google Scholar
61. De Curtis, M & Rigo, J (2012) The nutrition of preterm infants. Early Hum Dev 88, S5S7.Google Scholar
62. Gura, KM, Lee, S, Valim, C, et al. (2008) Safety and efficacy of a fish-oil-based fat emulsion in the treatment of parenteral nutrition-associated liver disease. Pediatrics 121, e678e686.Google Scholar
63. de Meijer, VE, Gura, KM, Le, HD, et al. (2009) Fish oil-based lipid emulsions prevent and reverse parenteral nutrition-associated liver disease: the Boston experience. JPEN J Parenter Enteral Nutr 33, 541547.Google Scholar
64. Wu, WZ, Wang, XQ, Wu, GY, et al. (2010) Differential composition of proteomes in sow colostrum and milk from anterior and posterior mammary glands. J Anim Sci 88, 26572664.Google Scholar
65. Ziegler, EE (2011) Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 58, Suppl. 1, 818.CrossRefGoogle ScholarPubMed
66. Kuschel, CA & Harding, JE (2004) Multicomponent fortified human milk for promoting growth in preterm infants. Cochrane Database Syst Rev, issue 1, CD000343.Google Scholar
67. Groh-Wargo, S & Sapsford, A (2009) Enteral nutrition support of the preterm infant in the neonatal intensive care unit. Nutr Clin Pract 24, 363376.Google Scholar
68. Hay, WW Jr & Hendrickson, KC (2017) Preterm formula use in the preterm very low birth weight infant. Semin Fetal Neonatal Med 22, 1522.Google Scholar
69. Tan-Dy, CR & Ohlsson, A (2013) Lactase treated feeds to promote growth and feeding tolerance in preterm infants. Cochrane Database Syst Rev, issue 3, CD004591.Google Scholar
70. Dollberg, S, Kuint, J, Mazkereth, R, et al. (2000) Feeding tolerance in preterm infants: randomized trial of bolus and continuous feeding. J Am Coll Nutr 19, 797800.Google Scholar
71. Schanler, RJ, Shulman, RJ, Lau, C, et al. (1999) Feeding strategies for premature infants: randomized trial of gastrointestinal priming and tube-feeding method. Pediatrics 103, 434439.Google Scholar
72. Gazzaneo, MC, Suryawan, A, Orellana, RA, et al. (2011) Intermittent bolus feeding has a greater stimulatory effect on protein synthesis in skeletal muscle than continuous feeding in neonatal pigs. J Nutr 141, 21522158.Google Scholar
73. El-Kadi, SW, Gazzaneo, MC, Suryawan, A, et al. (2013) Viscera and muscle protein synthesis in neonatal pigs is increased more by intermittent bolus than by continuous feeding. Pediatr Res 74, 154162.Google Scholar
74. Premji, SS & Chessell, L (2011) Continuous nasogastric milk feeding versus intermittent bolus milk feeding for premature infants less than 1500 grams. Cochrane Database Syst Rev, issue 11, CD001819.Google Scholar
75. Dsilna, A, Christensson, K, Alfredsson, L, et al. (2005) Continuous feeding promotes gastrointestinal tolerance and growth in very low birth weight infants. J Pediatr 147, 4349.Google Scholar
76. Dsilna, A, Christensson, K, Gustafsson, AS, et al. (2008) Behavioral stress is affected by the mode of tube feeding in very low birth weight infants. Clin J Pain 24, 447455.Google Scholar
77. Kashyap, S, Schulze, KF, Forsyth, M, et al. (1988) Growth, nutrient retention, and metabolic response in low birth weight infants fed varying intakes of protein and energy. J Pediatr 113, 713721.Google Scholar
78. Kashyap, S, Ohira-Kist, K, Abildskov, K, et al. (2001) Effects of quality of energy intake on growth and metabolic response of enterally fed low-birth-weight infants. Pediatr Res 50, 390397.Google Scholar
79. Premji, SS, Fenton, TR & Sauve, RS (2006) Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev, issue 1, CD003959.Google Scholar
80. Albertssonwikland, K, Wennergren, G, Wennergren, M, et al. (1993) Longitudinal follow-up of growth in children born small-for-gestational-age. Acta Paediatr 82, 438443.Google Scholar
81. Thureen, P & Heird, WC (2005) Protein and energy requirements of the preterm/low birthweight (LBW) infant. Pediatr Res 57, 95R98R.Google Scholar
82. Fenton, TR, Premji, SS, Al-Wassia, H, et al. (2014) Higher versus lower protein intake in formula-fed low birth weight infants. Cochrane Database Syst Rev, issue 4, CD003959.Google Scholar
83. Young, L, Morgan, J, McCormick, FM, et al. (2012) Nutrient-enriched formula versus standard term formula for preterm infants following hospital discharge. Cochrane Database Syst Rev, issue 3, CD004696.Google Scholar
84. Morise, A, Seve, B, Mace, K, et al. (2011) Growth, body composition and hormonal status of growing pigs exhibiting a normal or small weight at birth and exposed to a neonatal diet enriched in proteins. Br J Nutr 105, 14711479.CrossRefGoogle ScholarPubMed
85. Han, F (2014) High nutrient intake alters muscular growth and metabolic status of neonatal intra-uterine growth-retarded pigs. 2014 ADSA-ASAS-CSAS Joint Annual Meeting, 20-24 July 2014.Google Scholar
86. Weinkove, C, Weinkove, EA & Pimstone, BL (1974) Insulin release and pancreatic-islet volume in malnourished rats. S Afr Med J 48, 18881888.Google Scholar
87. Feillet-Coudray, C, Sutra, T, Fouret, G, et al. (2009) Oxidative stress in rats fed a high-fat high-sucrose diet and preventive effect of polyphenols: Involvement of mitochondrial and NAD(P)H oxidase systems. Free Radic Biol Med 46, 624632.Google Scholar
88. Decorde, K, Teissedre, PL, Sutra, T, et al. (2009) Chardonnay grape seed procyanidin extract supplementation prevents high-fat diet-induced obesity in hamsters by improving adipokine imbalance and oxidative stress markers. Mol Nutr Food Res 53, 659666.Google Scholar
89. Devaraj, S, Wang-Polagruto, J, Polagruto, J, et al. (2008) High-fat, energy-dense, fast-food-style breakfast results in an increase in oxidative stress in metabolic syndrome. Metabolism 57, 867870.Google Scholar
90. Hracsko, Z, Orvos, H, Novak, Z, et al. (2008) Evaluation of oxidative stress markers in neonates with intra-uterine growth retardation. Redox Rep 13, 1116.Google Scholar
91. Wang, J, Wu, Z, Li, D, et al. (2012) Nutrition, epigenetics, and metabolic syndrome. Antioxid Redox Signal 17, 282301.Google Scholar
92. Wang, W, Degroote, J, Van Ginneken, C, et al. (2016) Intrauterine growth restriction in neonatal piglets affects small intestinal mucosal permeability and mRNA expression of redox-sensitive genes. FASEB J 30, 863873.Google Scholar
93. Desai, M, Gayle, D, Babu, J, et al. (2005) Programmed obesity in intrauterine growth-restricted newborns: modulation by newborn nutrition. Am J Physiol Regul Integr Comp Physiol 288, R91R96.Google Scholar
94. Dai, Y, Thamotharan, S, Garg, M, et al. (2012) Superimposition of postnatal calorie restriction protects the aging male intrauterine growth-restricted offspring from metabolic maladaptations. Endocrinology 153, 42164226.Google Scholar
95. Garg, M, Thamotharan, M, Dai, Y, et al. (2013) Glucose intolerance and lipid metabolic adaptations in response to intrauterine and postnatal calorie restriction in male adult rats. Endocrinology 154, 102113.Google Scholar
96. Che, LQ, Xuan, Y, Hu, L, et al. (2015) Effect of Postnatal nutrition restriction on the oxidative status of neonates with intrauterine growth restriction in a pig model. Neonatology 107, 9399.Google Scholar
97. Hu, L, Liu, Y, Yan, C, et al. (2015) Postnatal nutritional restriction affects growth and immune function of piglets with intra-uterine growth restriction. Br J Nutr 114, 5362.Google Scholar
98. Hay, WW Jr, Brown, LD & Denne, SC (2014) Energy requirements, protein-energy metabolism and balance, and carbohydrates in preterm infants. World Rev Nutr Diet 110, 6481.Google Scholar
99. Kashyap, S (2007) Enteral intake for very low birth weight infants: what should the composition be? Semin Perinatol 31, 7482.Google Scholar
100. Raiha, NC, Fazzolari-Nesci, A, Cajozzo, C, et al. (2002) Whey predominant, whey modified infant formula with protein/energy ratio of 1.8 g/100 kcal: adequate and safe for term infants from birth to four months. J Pediatr Gastroenterol Nutr 35, 275281.Google Scholar
101. Su, BH (2014) Optimizing nutrition in preterm infants. Pediatr Neonatol 55, 513.Google Scholar
102. Belfort, MB, Gillman, MW, Buka, SL, et al. (2013) Preterm infant linear growth and adiposity gain: trade-offs for later weight status and intelligence quotient. J Pediatr 163, 15641569.Google Scholar
103. Sanz-Cortes, M, Carbajo, RJ, Crispi, F, et al. (2013) Metabolomic profile of umbilical cord blood plasma from early and late intrauterine growth restricted (IUGR) neonates with and without signs of brain vasodilation. PLOS ONE 8, e80121.Google Scholar
104. Ivorra, C, Garcia-Vicent, C, Chaves, FJ, et al. (2012) Metabolomic profiling in blood from umbilical cords of low birth weight newborns. J Transl Med 10, 142.Google Scholar
105. Tea, I, Le Gall, G, Küster, A, et al. (2012) 1H-NMR-based metabolic profiling of maternal and umbilical cord blood indicates altered materno-foetal nutrient exchange in preterm infants. PLOS ONE 7, e29947.Google Scholar
106. Lin, G, Liu, C, Feng, C, et al. (2012) Metabolomic analysis reveals differences in umbilical vein plasma metabolites between normal and growth-restricted fetal pigs during late gestation. J Nutr 142, 990998.Google Scholar
107. Wu, G, Bazer, FW, Johnson, GA, et al. (2011) Triennial growth symposium: important roles for L-glutamine in swine nutrition and production. J Anim Sci 89, 20172030.Google Scholar
108. Alexandre-Gouabau, MC, Courant, F, Le Gall, G, et al. (2011) Offspring metabolomic response to maternal protein restriction in a rat model of intrauterine growth restriction (IUGR). J Proteome Res 10, 32923302.Google Scholar
109. Flynn, NE, Meininger, CJ, Haynes, TE, et al. (2002) The metabolic basis of arginine nutrition and pharmacotherapy. Biomed Pharmacother 56, 427438.Google Scholar
110. Visek, WJ (1986) Arginine needs, physiological state and usual diets. A reevaluation. J Nutr 116, 3646.Google Scholar
111. Southern, LL & Baker, DH (1983) Arginine requirement of the young pig. J Anim Sci 57, 402412.Google Scholar
112. Wu, GY, Knabe, DA & Kim, SW (2004) Arginine nutrition in neonatal pigs. J Nutr 134, 2783s2790s.Google Scholar
113. Kim, SW & Wu, G (2004) Dietary arginine supplementation enhances the growth of milk-fed young pigs. J Nutr 134, 625630.Google Scholar
114. Wu, GY & Morris, SM (1998) Arginine metabolism: nitric oxide and beyond. Biochem J 336, 117.Google Scholar
115. Zhang, Z, Adelman, AS, Rai, D, et al. (2013) Amino acid profiles in term and preterm human milk through lactation: a systematic review. Nutrients 5, 48004821.Google Scholar
116. Hill, PD, Aldag, JC, Chatterton, RT, et al. (2005) Comparison of milk output between mothers of preterm and term infants: the first 6 weeks after birth. J Hum Lact 21, 2230.Google Scholar
117. Tomlinson, C, Rafii, M, Sgro, M, et al. (2011) Arginine is synthesized from proline, not glutamate, in enterally fed human preterm neonates. Pediatr Res 69, 4650.Google Scholar
118. Neu, J (2002) Arginine supplementation and the prevention of necrotizing enterocolitis in very low birth weight infants. J Pediatr 140, 389391.Google Scholar
119. Mitchell, K, Lyttle, A, Amin, H, et al. (2014) Arginine supplementation in prevention of necrotizing enterocolitis in the premature infant: an updated systematic review. BMC Pediatrics 14, 226.Google Scholar
120. Shah, P & Shah, V (2007) Arginine supplementation for prevention of necrotising enterocolitis in preterm infants. Cochrane Database Syst Rev, issue 3, CD004339.Google Scholar
121. Getty, CM, Almeida, FN, Baratta, AA, et al. (2015) Plasma metabolomics indicates metabolic perturbations in low birth weight piglets supplemented with arginine. J Anim Sci 93, 57545763.CrossRefGoogle ScholarPubMed
122. Wang, X, Qiao, S, Yin, Y, et al. (2007) A deficiency or excess of dietary threonine reduces protein synthesis in jejunum and skeletal muscle of young pigs. J Nutr 137, 14421446.Google Scholar
123. Wu, G, Bazer, FW & Tou, W (1995) Developmental changes of free amino acid concentrations in fetal fluids of pigs. J Nutr 125, 28592868.Google Scholar
124. Horio, Y, Osawa, S, Takagaki, K, et al. (2008) Glutamine supplementation increases Th1-cytokine responses in murine intestinal intraepithelial lymphocytes. Cytokine 44, 9295.Google Scholar
125. Wu, G (1998) Intestinal mucosal amino acid catabolism. J Nutr 128, 12491252.Google Scholar
126. Wu, G (2010) Functional amino acids in growth, reproduction, and health. Adv Nutr 1, 3137.Google Scholar
127. Korkmaz, A, Yurdakok, M, Yigit, S, et al. (2007) Long-term enteral glutamine supplementation in very low birth weight infants: effects on growth parameters. Turk J Pediatr 49, 3744.Google Scholar
128. Neu, J, Roig, JC, Meetze, WH, et al. (1997) Enteral glutamine supplementation for very low birth weight infants decreases morbidity. J Pediatr 131, 691699.Google Scholar
129. van den Berg, A, van Elburg, RM, Westerbeek, EA, et al. (2005) Glutamine-enriched enteral nutrition in very-low-birth-weight infants and effects on feeding tolerance and infectious morbidity: a randomized controlled trial. Am J Clin Nutr 81, 13971404.Google Scholar
130. Vaughn, P, Thomas, P, Clark, R, et al. (2003) Enteral glutamine supplementation and morbidity in low birth weight infants. J Pediatr 142, 662668.Google Scholar
131. Zhong, X, Li, W, Huang, X, et al. (2012) Effects of glutamine supplementation on the immune status in weaning piglets with intrauterine growth retardation. Arch Anim Nutr 66, 347356.Google Scholar
132. Davis, TA, Fiorotto, ML, Burrin, DG, et al. (2002) Stimulation of protein synthesis by both insulin and amino acids is unique to skeletal muscle in neonatal pigs. Am J Physiol Endocrinol Metab 282, E880E890.Google Scholar
133. Lei, J, Feng, D, Zhang, Y, et al. (2012) Nutritional and regulatory role of branched-chain amino acids in lactation. Front Biosci 17, 27252739.Google Scholar
134. Rezaei, R, Wang, W, Wu, Z, et al. (2013) Biochemical and physiological bases for utilization of dietary amino acids by young pigs. J Anim Sci Biotechnol 4, 7.Google Scholar
135. Yuan, TL, Zhu, YH, Shi, M, et al. (2015) Within-litter variation in birth weight: impact of nutritional status in the sow. J Zhejiang Univ Sci B 16, 417435.Google Scholar
136. Xu, W, Bai, K, He, J, et al. (2016) Leucine improves growth performance of intrauterine growth retardation piglets by modifying gene and protein expression related to protein synthesis. Nutrition 32, 114121.Google Scholar
137. Zheng, C, Huang, C, Cao, Y, et al. (2009) Branched-chain amino acids reverse the growth of intrauterine growth retardation rats in a malnutrition model. Asian-Australas J Anim Sci 22, 14951503.Google Scholar
138. Teodoro, GFR, Vianna, D, Torres-Leal, FL, et al. (2012) Leucine is essential for attenuating fetal growth restriction caused by a protein-restricted diet in rats. J Nutr 142, 924930.Google Scholar
139. Keller, J, Ringseis, R, Priebe, S, et al. (2011) Dietary L-carnitine alters gene expression in skeletal muscle of piglets. Mol Nutr Food Res 55, 419429.Google Scholar
140. Whitfield, J, Smith, T, Sollohub, H, et al. (2003) Clinical effects of L-carnitine supplementation on apnea and growth in very low birth weight infants. Pediatrics 111, 477482.Google Scholar
141. Owen, KQ, Nelssen, JL, Goodband, RD, et al. (2001) Effect of dietary L-carnitine on growth performance and body composition in nursery and growing-finishing pigs. J Anim Sci 79, 15091515.Google Scholar
142. Owen, KQ, Nelssen, JL, Goodband, RD, et al. (1996) Effect of L-carnitine and soybean oil on growth performance and body composition of early-weaned pigs. J Anim Sci 74, 16121619.Google Scholar
143. Keller, J, Ringseis, R, Koc, A, et al. (2012) Supplementation with l-carnitine downregulates genes of the ubiquitin proteasome system in the skeletal muscle and liver of piglets. Animal 6, 7078.Google Scholar
144. Losel, D, Kalbe, C & Rehfeldt, C (2009) L-Carnitine supplementation during suckling intensifies the early postnatal skeletal myofiber formation in piglets of low birth weight. J Anim Sci 87, 22162226.Google Scholar
145. Innis, SM (2005) Essential fatty acid transfer and fetal development. Placenta 26, S70S75.Google Scholar
146. Salem, N, Wegher, B, Mena, P, et al. (1996) Arachidonic and docosahexaenoic acids are biosynthesized from their 18-carbon precursors in human infants. Proc Natl Acad Sci U S A 93, 4954.Google Scholar
147. Uauy, R, Mena, P, Wegher, B, et al. (2000) Long chain polyunsaturated fatty acid formation in neonates: effect of gestational age and intrauterine growth. Pediatr Res 47, 127135.Google Scholar
148. Carnielli, VP, Wattimena, DJL, Luijendijk, IHT, et al. (1996) The very low birth weight premature infant is capable of synthesizing arachidonic and docosahexaenoic acids from linoleic and linolenic acids. Pediatr Res 40, 169174.Google Scholar
149. Fleith, M & Clandinin, MT (2005) Dietary PUFA for preterm and term infants: review of clinical studies. Crit Rev Food Sci Nutr 45, 205229.Google Scholar
150. Uauy, R & Mena, P (2015) Long-chain polyunsaturated fatty acids supplementation in preterm infants. Curr Opin Pediatr 27, 165171.Google Scholar
151. Cetin, I, Giovannini, N, Alvino, G, et al. (2002) Intrauterine growth restriction is associated with changes in polyunsaturated fatty acid fetal-maternal relationships. Pediatr Res 52, 750755.Google Scholar
152. Groh-Wargo, S, Jacobs, J, Auestad, N, et al. (2005) Body composition in preterm infants who are fed long-chain polyunsaturated fatty acids: a prospective, randomized, controlled trial. Pediatr Res 57, 712718.Google Scholar
153. Zhang, P, Lavoie, PM, Lacaze-Masmonteil, T, et al. (2014) Omega-3 long-chain polyunsaturated fatty acids for extremely preterm infants: a systematic review. Pediatrics 134, 120134.Google Scholar
154. Yeung, MY (2006) Postnatal growth, neurodevelopment and altered adiposity after preterm birth--from a clinical nutrition perspective. Acta Paediatr 95, 909917.Google Scholar
155. Azain, MJ (2004) Role of fatty acids in adipocyte growth and development. J Anim Sci 82, 916924.Google Scholar
156. Ruzickova, J, Rossmeisl, M, Prazak, T, et al. (2004) Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue. Lipids 39, 11771185.Google Scholar
157. Clifton, PM & Nestel, PJ (1998) Relationship between plasma insulin and erythrocyte fatty acid composition. Prostaglandins Leukot Essent Fatty Acids 59, 191194.Google Scholar
158. Das, UN (2002) Is metabolic syndrome X an inflammatory condition? Exp Biol Med 227, 989997.Google Scholar
159. Sauer, N, Mosenthin, R & Bauer, E (2011) The role of dietary nucleotides in single-stomached animals. Nutr Res Rev 24, 4659.Google Scholar
160. Uauy, R (1989) Dietary nucleotides and requirements in early life. In Textbook of Gastroenterology and Nutrition in Infancy, 2nd ed. pp. 265280 [E Lebenthal, editor]. New York: Raven Press.Google Scholar
161. Sauer, N, Eklund, M, Bauer, E, et al. (2012) The effects of pure nucleotides on performance, humoral immunity, gut structure and numbers of intestinal bacteria of newly weaned pigs. J Anim Sci 90, 31263134.Google Scholar
162. Che, L, Hu, L, Liu, Y, et al. (2016) Dietary nucleotides supplementation improves the intestinal development and immune function of neonates with intra-uterine growth restriction in a pig model. PLOS ONE 11, e0157314.Google Scholar
163. Savaiano, DA & Clifford, AJ (1981) Adenine, the precursor of nucleic acids in intestinal cells unable to synthesize purines de novo . J Nutr 111, 18161822.Google Scholar
164. Lapillonne, A, Salle, BL, Glorieux, FH, et al. (2004) Bone mineralization and growth are enhanced in preterm infants fed an isocaloric, nutrient-enriched preterm formula through term. Am J Clin Nutr 80, 15951603.Google Scholar
165. Silverwood, RJ, Pierce, M, Hardy, R, et al. (2013) Low birth weight, later renal function, and the roles of adulthood blood pressure, diabetes, and obesity in a British birth cohort. Kidney Int 84, 12621270.Google Scholar
166. Kositamongkol, S, Suthutvoravut, U, Chongviriyaphan, N, et al. (2011) Vitamin A and E status in very low birth weight infants. J Perinatol 31, 471476.Google Scholar
167. Agarwal, R, Virmani, D, Jaipal, ML, et al. (2012) Vitamin D status of low birth weight infants in Delhi: a comparative study. J Trop Pediatr 58, 446450.Google Scholar
168. Mactier, H & Weaver, LT (2005) Vitamin A and preterm infants: what we know, what we don’t know, and what we need to know. Arch Dis Child Fetal Neonatal Ed 90, 103108.Google Scholar
169. Darlow, BA & Graham, PJ (2007) Vitamin A supplementation to prevent mortality and short and long-term morbidity in very low birthweight infants. Cochrane Database Syst Rev, issue 4, CD000501.Google Scholar
170. Brion, LP, Bell, EF & Raghuveer, TS (2003) Vitamin E supplementation for prevention of morbidity and mortality in preterm infants. Cochrane Database Syst Rev, issue 3, CD003665.Google Scholar
171. Natarajan, CK, Sankar, MJ, Agarwal, R, et al. (2014) Trial of daily vitamin D supplementation in preterm infants. Pediatrics 133, e628e634.Google Scholar
172. Senterre, J, Putet, G, Salle, B, et al. (1983) Effects of vitamin D and phosphorus supplementation on calcium retention in preterm infants fed banked human milk. J Pediatr 103, 305307.Google Scholar
173. Mathur, NB, Saini, A & Mishra, TK (2016) Assessment of adequacy of supplementation of vitamin D in very low birth weight preterm neonates: a randomized controlled trial. J Trop Pediatr 62, 429435.Google Scholar
174. Palmer, C, Bik, EM, DiGiulio, DB, et al. (2007) Development of the human infant intestinal microbiota. PLoS Biol 5, e177.Google Scholar
175. Sari, FN, Dizdar, EA, Oguz, S, et al. (2011) Oral probiotics: Lactobacillus sporogenes for prevention of necrotizing enterocolitis in very low-birth weight infants: a randomized, controlled trial. Eur J Clin Nutr 65, 434439.Google Scholar
176. Oncel, MY, Arayici, S, Sari, FN, et al. (2015) Comparison of Lactobacillus reuteri and nystatin prophylaxis on Candida colonization and infection in very low birth weight infants. J Matern Fetal Neonatal Med 28, 17901794.Google Scholar
177. Hartel, C, Pagel, J, Rupp, J, et al. (2014) Prophylactic use of Lactobacillus acidophilus/Bifidobacterium infantis probiotics and outcome in very low birth weight infants. J Pediatr 165, 285289.e281.Google Scholar
178. Yamasaki, C, Totsu, S, Uchiyama, A, et al. (2012) Effect of Bifidobacterium administration on very-low-birthweight infants. Pediatr Int 54, 651656.Google Scholar
179. Li, Y, Shimizu, T, Hosaka, A, et al. (2004) Effects of Bifidobacterium breve supplementation on intestinal flora of low birth weight infants. Pediatr Int 46, 509515.Google Scholar
180. Wang, Q, Dong, J & Zhu, Y (2012) Probiotic supplement reduces risk of necrotizing enterocolitis and mortality in preterm very low-birth-weight infants: an updated meta-analysis of 20 randomized, controlled trials. J Pediatr Surg 47, 241248.Google Scholar
181. Marques, TM, Wall, R, Ross, RP, et al. (2010) Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol 21, 149156.Google Scholar
182. Chapman, CM, Gibson, GR & Rowland, I (2011) Health benefits of probiotics: are mixtures more effective than single strains? Eur J Nutr 50, 117.Google Scholar
183. Braga, TD, da Silva, GA, de Lira, PI, et al. (2011) Efficacy of Bifidobacterium breve and Lactobacillus casei oral supplementation on necrotizing enterocolitis in very-low-birth-weight preterm infants: a double-blind, randomized, controlled trial. Am J Clin Nutr 93, 8186.Google Scholar
184. Saengtawesin, V, Tangpolkaiwalsak, R & Kanjanapattankul, W (2014) Effect of oral probiotics supplementation in the prevention of necrotizing enterocolitis among very low birth weight preterm infants. J Med Assoc Thai 97, Suppl. 6, S20S25.Google Scholar
185. Lin, HC, Hsu, CH, Chen, HL, et al. (2008) Oral probiotics prevent necrotizing enterocolitis in very low birth weight preterm infants: a multicenter, randomized, controlled trial. Pediatrics 122, 693700.Google Scholar
186. Al-Hosni, M, Duenas, M, Hawk, M, et al. (2012) Probiotics-supplemented feeding in extremely low-birth-weight infants. J Perinatol 32, 253259.Google Scholar
187. Boehm, G, Lidestri, M, Casetta, P, et al. (2002) Supplementation of a bovine milk formula with an oligosaccharide mixture increases counts of faecal bifidobacteria in preterm infants. Arch Dis Child Fetal Neonatal Ed 86, F178F181.Google Scholar
188. Westerbeek, EA, van Elburg, RM, van den Berg, A, et al. (2008) Design of a randomised controlled trial on immune effects of acidic and neutral oligosaccharides in the nutrition of preterm infants: carrot study. BMC Pediatr 8, 46.Google Scholar
189. Riskin, A, Hochwald, O, Bader, D, et al. (2010) The effects of lactulose supplementation to enteral feedings in premature infants: a pilot study. J Pediatr 156, 209214.Google Scholar
190. Dilli, D, Aydin, B, Fettah, ND, et al. (2015) The propre-save study: effects of probiotics and prebiotics alone or combined on necrotizing enterocolitis in very low birth weight infants. J Pediatr 166, 545551.e1.Google Scholar
191. Nandhini, LP, Biswal, N, Adhisivam, B, et al. (2016) Synbiotics for decreasing incidence of necrotizing enterocolitis among preterm neonates – a randomized controlled trial. J Matern Fetal Neonatal Med 29, 821825.Google Scholar
192. Gautron, L & Elmquist, JK (2011) Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 121, 20872093.Google Scholar
193. Djiane, J & Attig, L (2008) Role of leptin during perinatal metabolic programming and obesity. J Physiol Pharmacol 59, Suppl. 1, 5563.Google Scholar
194. Attig, L, Djiane, J, Gertler, A, et al. (2008) Study of hypothalamic leptin receptor expression in low-birth-weight piglets and effects of leptin supplementation on neonatal growth and development. Am J Physiol Endocrinol Metab 295, E1117E1125.Google Scholar
195. Jaquet, D, Leger, J, Levy-Marchal, C, et al. (1998) Ontogeny of leptin in human fetuses and newborns: effect of intrauterine growth retardation on serum leptin concentrations. J Clin Endocrinol Metab 83, 12431246.Google Scholar
196. Morise, A, Seve, B, Mace, K, et al. (2009) Impact of intrauterine growth retardation and early protein intake on growth, adipose tissue, and the insulin-like growth factor system in piglets. Pediatr Res 65, 4550.Google Scholar
197. Shulman, RJ (1990) Oral insulin increases small intestinal mass and disaccharidase activity in the newborn miniature pig. Pediatr Res 28, 171175.Google Scholar
198. Xu, RJ, Mellor, DJ, Birtles, MJ, et al. (1994) Effects of oral IGF-I or IGF-II on digestive organ growth in newborn piglets. Biol Neonate 66, 280287.Google Scholar
199. Houle, VM, Schroeder, EA, Odle, J, et al. (1997) Small intestinal disaccharidase activity and ileal villus height are increased in piglets consuming formula containing recombinant human insulin-like growth factor-I. Pediatr Res 42, 7886.Google Scholar
200. Burrin, DG, Wester, TJ, Davis, TA, et al. (1996) Orally administered IGF-I increases intestinal mucosal growth in formula-fed neonatal pigs. Am J Physiol 270, R1085R1091.Google Scholar
201. Schoknecht, PA, Ebner, S, Skottner, A, et al. (1997) Exogenous insulin-like growth factor-I increases weight gain in intrauterine growth-retarded neonatal pigs. Pediatr Res 42, 201207.Google Scholar
202. Beardsall, K, Ogilvy-Stuart, AL, Frystyk, J, et al. (2007) Early elective insulin therapy can reduce hyperglycemia and increase insulin-like growth factor-I levels in very low birth weight infants. J Pediatr 151, 611617.e611.Google Scholar
203. Fritz, JV, Desai, MS, Shah, P, et al. (2013) From meta-omics to causality: experimental models for human microbiome research. Microbiome 1, 14.Google Scholar
204. Meurens, F, Summerfield, A, Nauwynck, H, et al. (2012) The pig: a model for human infectious diseases. Trends Microbiol 20, 5057.Google Scholar
Figure 0

Table 1 Examples of epidemiological and animal studies that reveal alterations in vital organs of low birth weight (LBW) offspring compared with normal ones

Figure 1

Table 2 Examples of nutrition strategies for improving growth, development and health of low birth weight (LBW) infants