Effects of dietary nucleotide supplementation on growth in infants: a meta-analysis of randomized controlled trials

  • Lanfang Wang
  • Shu Mu
  • Xiaoyan Xu
  • Zhexi Shi
  • Li Shen
Original Contribution



Dietary nucleotides are thought to be conditionally essential nutrients in infancy. However, studies have reported inconsistent findings regarding the association between nucleotide supplementation and infant physical growth. We conducted this meta-analysis to examine the efficacy of nucleotide supplementation of infant formula in promoting early infant growth.


Randomized controlled trials that evaluated the association between nucleotide supplementation and infant growth through June 2017 were included. Study quality was assessed using the Cochrane Collaboration’s Risk of Bias tool. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using Q and I2 tests.


Nucleotide supplementation significantly increased the rate of weight gain (SMD 0.26; 95% CI 0.06–0.47), but had no effect on weight (SMD − 0.16; 95% CI − 0.55–0.23), weight Z score (SMD, − 0.42; 95% CI − 1.64–0.81), length (SMD 0.01; 95% CI − 0.18–0.21) and length Z score (SMD 0.15; 95% CI − 0.10–0.40). Occipitofrontal head circumference (OFC) at 7–8 weeks (SMD 0.30; 95% CI 0.10–0.50) and the rate of OFC gain (SMD 0.34; 95% CI 0.09–0.58) were significantly improved with nucleotide supplementation, whereas, 16- and 20-week OFC values did not differ.


Our meta-analysis indicated that nucleotide supplementation can increase the rate of weight gain, OFC and rate of OFC gain; however, we cannot conclude that it affects weight, weight Z score, length or length Z score. Large-scale randomized controlled trials of long-term nucleotide supplementation are needed to reach definitive conclusions.


Nucleotides Meta-analysis Growth Infant formula 



This work was supported by the National Natural Science Foundation of China [Grant Number 31101720] and the National High Technology Research and Development Program of China (863 Program) [Grant Number 2015AA021002].

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interests regarding the publication of this article.


  1. 1.
    Walker A (2010) Breast milk as the gold standard for protective nutrients. J Pediatr 156(2 Suppl):S3–S7. Google Scholar
  2. 2.
    Barness LA (1994) Dietary sources of nucleotides—from breast milk to weaning. J Nutr 124(1 Suppl):128s–130sCrossRefGoogle Scholar
  3. 3.
    Carver JD (1999) Dietary nucleotides: effects on the immune and gastrointestinal systems. Acta Paediatr Suppl 88(430):83–88CrossRefGoogle Scholar
  4. 4.
    Sanchez-Pozo A, Gil A (2002) Nucleotides as semiessential nutritional components. Br J Nutr 87(Suppl 1):S135–S137Google Scholar
  5. 5.
    Yu VY (2002) Scientific rationale and benefits of nucleotide supplementation of infant formula. J Paediatr Child Health 38(6):543–549CrossRefGoogle Scholar
  6. 6.
    Gutierrez-Castrellon P, Mora-Magana I, Diaz-Garcia L, Jimenez-Gutierrez C, Ramirez-Mayans J, Solomon-Santibanez GA (2007) Immune response to nucleotide-supplemented infant formulae: systematic review and meta-analysis. Brit J Nutr 98:S64–S67. CrossRefGoogle Scholar
  7. 7.
    Hawkes JS, Gibson RA, Roberton D, Makrides M (2006) Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial. Eur J Clin Nutr 60(2):254–264. CrossRefGoogle Scholar
  8. 8.
    Wang L, Liu J, Lv H, Zhang X, Shen L (2015) Effects of nucleotides supplementation of infant formulas on plasma and erythrocyte fatty acid composition: a meta-analysis. PLoS One 10(6):e0127758. CrossRefGoogle Scholar
  9. 9.
    Singhal A, Macfarlane GT, Macfarlane S, Lanigan J, Kennedy K, Elias-Jones A, Stephenson T, Dudek P, Lucas A (2008) Dietary nucleotides and fecal microbiota in formula-fed infants: a randomized controlled trial. Am J Clin Nutr 87(6):1785–1792CrossRefGoogle Scholar
  10. 10.
    Rodriguez-Serrano F, Marchal JA, Rios A, Martinez-Amat A, Boulaiz H, Prados J, Peran M, Caba O, Carrillo E, Hita F, Aranega A (2007) Exogenous nucleosides modulate proliferation of rat intestinal epithelial IEC-6 cells. J Nutr 137(4):879–884CrossRefGoogle Scholar
  11. 11.
    Maria Vieites J, Torre Rde L, Ramirez Mdel C, Torres MI, Sanchez-Pozo A, Gil A, Suarez A (2008) Exogenous nucleosides accelerate differentiation of rat intestinal epithelial cells. Br J Nutr 99(4):732–738. CrossRefGoogle Scholar
  12. 12.
    Carver JD, Stromquist CI (2006) Dietary nucleotides and preterm infant nutrition. J Perinatol 26(7):443–444. CrossRefGoogle Scholar
  13. 13.
    Cosgrove M, Davies DP, Jenkins HR (1996) Nucleotide supplementation and the growth of term small for gestational age infants. Arch Dis Child Fetal Neonatal Ed 74(2):F122–125CrossRefGoogle Scholar
  14. 14.
    Singhal A, Kennedy K, Lanigan J, Clough H, Jenkins W, Elias-Jones A, Stephenson T, Dudek P, Lucas A (2010) Dietary nucleotides and early growth in formula-fed infants: a randomized controlled trial. Pediatrics 126(4):e946–e953. CrossRefGoogle Scholar
  15. 15.
    Cooper PA, Bolton KD, Mokhachane M, Velaphi SC, Mphahlele RM, Bomela HN, Monaheng L, Roux P, Haschke-Becher E (2010) Growth of infants born to HIV-positive mothers fed a whey-adapted acidified starter formula with prebiotics and nucleotides: original research. 23 (2):90–95Google Scholar
  16. 16.
    Siahanidou T, Mandyla H, Papassotiriou I, Anagnostakis D (2004) Serum lipids in preterm infants fed a formula supplemented with nucleotides. J Pediatr Gastroenterol Nutr 38(1):56–60CrossRefGoogle Scholar
  17. 17.
    Pita ML, Fernandez MR, De-Lucchi C, Medina A, Martinez-Valverde A, Uauy R, Gil A (1988) Changes in the fatty acids pattern of red blood cell phospholipids induced by type of milk, dietary nucleotide supplementation, and postnatal age in preterm infants. J Pediatr Gastroenterol Nutr 7(5):740–747CrossRefGoogle Scholar
  18. 18.
    Hernell O, Lonnerdal B (2002) Iron status of infants fed low-iron formula: no effect of added bovine lactoferrin or nucleotides. Am J Clin Nutr 76(4):858–864CrossRefGoogle Scholar
  19. 19.
    Axelsson I, Flodmark CE, Raiha N, Tacconi M, Visentin M, Minoli I, Moro G, Warm A (1997) The influence of dietary nucleotides on erythrocyte membrane fatty acids and plasma lipids in preterm infants. Acta Paediatr 86(5):539–544CrossRefGoogle Scholar
  20. 20.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62(10):e1–e34. CrossRefGoogle Scholar
  21. 21.
    Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. Bmj 343:d5928. CrossRefGoogle Scholar
  22. 22.
    Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50(4):1088–1101CrossRefGoogle Scholar
  23. 23.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. Brit Med J 315(7109):629–634CrossRefGoogle Scholar
  24. 24.
    Wickett JC, Vernon PA, Lee DH (2000) Relationships between factors of intelligence and brain volume. Pers Indiv Differ 29(6):1095–1122. CrossRefGoogle Scholar
  25. 25.
    Gale CR, O’Callaghan FJ, Godfrey KM, Law CM, Martyn CN (2004) Critical periods of brain growth and cognitive function in children. Brain 127(Pt 2):321–329. CrossRefGoogle Scholar
  26. 26.
    Gale CR, O’Callaghan FJ, Bredow M, Martyn CN, Avon Longitudinal Study of P, Children Study T (2006) The influence of head growth in fetal life, infancy, and childhood on intelligence at the ages of 4 and 8 years. Pediatrics 118(4):1486–1492. CrossRefGoogle Scholar
  27. 27.
    Silva A, Metha Z, O’Callaghan FJ (2006) The relative effect of size at birth, postnatal growth and social factors on cognitive function in late childhood. Ann Epidemiol 16(6):469–476. CrossRefGoogle Scholar
  28. 28.
    Smithers LG, Lynch JW, Yang S, Dahhou M, Kramer MS (2013) Impact of neonatal growth on IQ and behavior at early school age. Pediatrics 132(1):e53–e60. CrossRefGoogle Scholar
  29. 29.
    Che L, Hu L, Liu Y, Yan C, Peng X, Xu Q, Wang R, Cheng Y, Chen H, Fang Z, Lin Y, Xu S, Feng B, Chen D, Wu D (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(6):e0157314. CrossRefGoogle Scholar
  30. 30.
    Sato N, Nakano T, Kawakami H, Idota T (1999) In vitro and in vivo effects of exogenous nucleotides on the proliferation and maturation of intestinal epithelial cells. J Nutr Sci Vitaminol (Tokyo) 45(1):107–118CrossRefGoogle Scholar
  31. 31.
    Ortega MA, Gil A, Sanchez-Pozo A (1995) Maturation status of small intestine epithelium in rats deprived of dietary nucleotides. Life Sci 56(19):1623–1630CrossRefGoogle Scholar
  32. 32.
    Uauy R, Stringel G, Thomas R, Quan R (1990) Effect of dietary nucleosides on growth and maturation of the developing gut in the rat. J Pediatr Gastroenterol Nutr 10(4):497–503CrossRefGoogle Scholar
  33. 33.
    LopezNavarro AT, Ortega MA, Peragon J, Bueno JD, Gil A, SanchezPozo A (1996) Deprivation of dietary nucleotides decreases protein synthesis in the liver and small intestine in rats. Gastroenterology 110(6):1760–1769. CrossRefGoogle Scholar
  34. 34.
    Guo X, Ran C, Zhang Z, He S, Jin M, Zhou Z (2017) The growth-promoting effect of dietary nucleotides in fish is associated with an intestinal microbiota-mediated reduction in energy expenditure. J Nutr. Google Scholar
  35. 35.
    Gil A, Corral E, Martinez A, Molina J (1986) Effects of the addition of nucleotides to an adapted milk formula on the microbial pattern of faeces in at term newborn infants. J Clin Nutr Gastroenterol 1:127–132Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lanfang Wang
    • 1
  • Shu Mu
    • 1
  • Xiaoyan Xu
    • 1
  • Zhexi Shi
    • 1
  • Li Shen
    • 2
  1. 1.Institute of Nutrition and Healthy FoodTongji University School of MedicineShanghaiChina
  2. 2.Department of Pathogen BiologyTongji University School of MedicineShanghaiChina

Personalised recommendations