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HiPP formula and nucleotides

Nucleotides are chemical compounds which act as the basic building blocks of DNA and RNA – they play an important role in cell growth and energy metabolism within the body. Undoubtedly, nucleotides are essential for human growth and function, but the reason for their presence is breast milk is unclear. 

The Scientific Committee on Food report (scientific basis for the EU-Directive)1 stated that “it's possible nucleotides in human milk are present as a by-product of milk synthesis, due to increased metabolic activity of the mammary tissue.” Additionally, in breast-fed infants the dietary intake of ready-formed nucleotides (from the milk) account for only a small percentage of their requirements; potentially as low as only 2%; and no more than 15% (Uauy et al 1994). It is not yet known what proportion of available nucleotides from human milk are able to be used by the infant. The low amounts of nucleotides present in human milk point to the view that infants are capable of effectively synthesizing their own nucleotides, and do not require them from the milk.  

Studies conducted on nucleotides added to formula milk are few and have shown mixed results: some of the studies have used nucleotide concentrations higher than is allowed in formula milk, so the results are not applicable to the lower concentrations found in these products.  

Due to the presence of nucleotides in breast milk, and the use of breast milk as a ‘gold standard’ template for formula milks; the Infant Formulae Directive allow nucleotides to be added to infant and follow-on formulas up to a total concentration of 5mg/100kcal, similar to the concentration of free ribonucleotides in human milk (4-6mg/100kcal). A suggested increase of this concentration from 5mg/100kcal to 16mg/100kcal was not recommended, due to an absence of demonstrable benefit of adding nucleotides to formula at these levels. It should be noted that the addition of nucleotides to infant formula is classed as ‘optional’ by both ESPGHAN (European Society for Paediatric Gastroenterology, Hepatology and Nutrition)12 and the EC-Directive on infant and follow-on formulae.  

One possible theory for the existence of nucleotides in human milk is their role in circadian rhythms, notably for sleep. It is thought that three nucleotides might be involved in the process of sleep (5’UMP, 5’GMP, 5’AMP).2 5’UMP has a depressive effect on the central nervous system and low doses of this can produce an increase in the number of both REM and non-REM episodes of sleep3. 5’AMP is the nucleotide best known as a sleep inducer 4-7; it’s properties have been recognized for over 30 years 8. Sanchez et al.(2009) monitored the levels and behavior of each nucleotide in 30 human milk samples from mothers, over a 24 hour period2. He discovered that 5’AMP, 5’GMP, 5’CMP and 5’IMP have circadian rhythms (the first two peaking overnight and the latter two peaking during the day). 5’UMP did not show a circadian rhythm, but it’s levels increased at night. It was proposed that the nocturnal rise in levels of 5’AMP, 5’GMP and 5’UMP may play a part in the ‘hypnotic’ actions of breast milk. 
Breast milk is a heterogeneous fluid; its composition changes over time periods including throughout a day and even during a feed; reflecting the infant’s energy needs and tissue growth 2, 11.  The work of Sanchez et al. suggests maternal milk may prepare their babies for the changing environment through the action of nucleotides. Thus, nucleotide addition to formula milks without clear evidence of its benefit may be unknowingly influencing the circadian rhythms of infants. 

As an ‘optional’ ingredient, the addition of nucleotides within organic-certified products is not allowed unless it is from agricultural origin or is deemed to have proven benefits (or is legally required).  

In light of unclear evidence on the benefits of adding nucleotides to formula milks, their status as an ‘optional’ ingredient by ESPGHAN and the EC-Directive, the potential hypnotic actions of nucleotides in human milks and the organic regulations’ stance on ‘optional’ ingredient additions, HiPP infant formulae do not contain nucleotides. 

The situation will be reviewed periodically, in line with our principle of being led by the best breast milk research. 

References:
1. European Commission-Scientific Committee on Food S. Report of the Scientific Commission on Food on the revision of essential requirements of infant formulae and follow-on formulae  Brussels: SCF/CS/NUT/IF/65Final; 2003.
2. Sanchez CL, Cubero J, Sanchez J, Chanclon B, Rivero M, Rodriguez AB, et al. The possible role of human milk nucleotides as sleep inducers. Nutr Neurosci. 2009; 12(1): 2-8.
3. Kimura T, Ho IK, Yamamoto I. Uridine receptor: discovery and its involvement in sleep mechanism. Sleep. 2001; 24(3): 251-60.
4. Dunwiddie TV, Worth T. Sedative and anticonvulsant effects of adenosine analogs in mouse and rat. J Pharmacol Exp Ther. 1982; 220(1): 70-6.
5. Virus RM, Djuricic-Nedelson M, Radulovacki M, Green RD. The effects of adenosine and 2'-deoxycoformycin on sleep and wakefulness in rats. Neuropharmacology. 1983; 22(12A): 1401-4.
6. Radulovacki M. Role of adenosine in sleep in rats. Rev Clin Basic Pharm. 1985; 5(3-4): 327-39.
7. Porkka-Heiskanen T, Alanko L, Kalinchuk A, Stenberg D. Adenosine and sleep. Sleep Med Rev. 2002; 6(4): 321-32.
8. Haulica I, Ababei L, Branisteanu D, Topoliceanu F. Letter: Preliminary data on the possible hypnogenic role of adenosine. J Neurochem. 1973; 21(4): 1019-20.
9. Zhdanova IV, Simmons M, Marcus JN, Busza AC, Leclair OU, Taylor JA. Nocturnal increase in plasma cGMP levels in humans. J Biol Rhythms. 1999; 14(4): 307-13.
10. Zhdanova IV, Raz DJ. Effects of melatonin ingestion on cAMP and cGMP levels in human plasma. J Endocrinol. 1999; 163(3): 457-62.
11. Dupont C. Protein requirements during the first year of life. Am J Clin Nutr. 2003; 77(6): 1544S-9S.
12. Koletzko B, Baker S, Cleghorn G, Neto UF, Gopalan S, Hernell O, et al. Global Standard for the Composition of Infant Formula: Recommendations of an ESPGHAN Coordinated International Expert Group. J Pediatr Gastroenterol Nutr. 2005; 41(5): 584-99.