Abstract
Short-term supplementation of non-human neutral and acidic oligosaccharides during the first postnatal weeks may enhance the maturation of the immune response in preterm infants and may lead to less allergic and infectious diseases during the first year of life. In a randomized controlled trial, 113 preterm infants (gestational age <32 weeks and/or birth weight <1500 g) were allocated to receive enteral neutral and acidic oligosaccharide supplementation or placebo between days 3 and 30 of life. The median age at follow-up was not different in both groups: 12 months corrected age (interquartile range [IQR], 11–15) in the prebiotic mixture group and 12 months corrected age in the placebo group (IQR, 10–19), respectively. In addition, baseline patient, maternal, and environmental characteristics were not different between the prebiotic mixture (n = 48) and placebo (n = 46) group. Incidence of allergic and infectious diseases was assessed by validated questionnaires. In total, 94/98 (96 %) of the eligible, surviving infants participated in this follow-up study. The incidence of atopic dermatitis (odds ratio [OR], 0.80; 95 % confidence interval [CI], 0.24–2.67), bronchial hyper-reactivity (OR, 1.04; 95 % CI, 0.38–2.87) and infections of the upper respiratory (OR, 0.95; 95 % CI, 0.37–2.44), lower respiratory (OR, 1.03; 95 % CI, 0.37–2.88), and gastrointestinal (OR, 1.77; 95 % CI, 0.55–5.73) tract was not different between the groups. Adjustment for potential confounding factors did not change the results of the primary analysis. Conclusion: Short-term enteral supplementation of non-human neutral and acidic oligosaccharides during the neonatal period in preterm infants does not decrease the incidence of allergic and infectious diseases during the first year of life.
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References
Arslanoglu S, Moro GE, Boehm G (2007) Early supplementation of prebiotic oligosaccharides protects formula-fed infants against infections during the first 6 months of life. J Nutr 137:2420–2424
Arslanoglu S, Moro GE, Schmitt J, Tandoi L, Rizzardi S, Boehm G (2008) Early dietary intervention with a mixture of prebiotic oligosaccharides reduces the incidence of allergic manifestations and infections during the first two years of life. J Nutr 138:1091–1095
Boehm G, Lidestri M, Casetta P, Jelinek J, Negretti F, Stahl B, Marini A (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:F178–F181
Boehm G, Stahl B (2002) Oligosaccharides. In: Mattila-Sandholm T (ed) Functional dairy products. Woodhead, Cambridge, pp 203–243
Brunekreef B, Smit J, de Jongste J, Neijens H, Gerritsen J, Postma D, Aalberse R, Koopman L, Kerkhof M, Wilga A, van Strien R (2002) The prevention and incidence of asthma and mite allergy (PIAMA) birth cohort study: design and first results. Pediatr Allergy Immunol Suppl 13 15:55–60
Bruzzese E, Volpicelli M, Squeglia V, Bruzzese D, Salvini F, Bisceglia M, Lionetti P, Cinquetti M, Iacono G, Amarri S, Guarino A (2009) A formula containing galacto- and fructo-oligosaccharides prevents intestinal and extra-intestinal infections: an observational study. Clin Nutr 28:156–161
Buhrer C, Grimmer I, Niggemann B, Obladen M (1999) Low 1-year prevalence of atopic eczema in very low birthweight infants. Lancet 353:1674
Decsi T, Arato A, Balogh M, Dolinay T, Kanjo AH, Szabo E, Varkonyi A (2005) Randomised placebo controlled double blind study on the effect of prebiotic oligosaccharides on intestinal flora in healthy infants. Orv Hetil 146:2445–2450
Eiwegger T, Stahl B, Haidl P, Schmitt J, Boehm G, Dehlink E, Urbanek R, Szepfalusi Z (2010) Prebiotic oligosaccharides: in vitro evidence for gastrointestinal epithelial transfer and immunomodulatory properties. Pediatr Allergy Immunol 21:1179–1188
Gruber C, van Stuijvenberg M, Mosca F, Moro G, Chirico G, Braegger C, Riedler J, Boehm G, Wahn U (2010) Reduced occurrence of early atopic dermatitis because of immunoactive prebiotics among low-atopy-risk infants. J Allergy Clin Immunol 126:791–797
Hofman A, Jaddoe VWV, Mackenbach JP, Moll HA, Snijders RFM, Steegers EAP, Verhulst FC, Witteman JCM, Buller HA (2004) Growth, development and health from early fetal life until young adulthood: the Generation R Study. Paediatr Perinat Epidemiol 18:61–72
Hooper LV (2004) Bacterial contributions to mammalian gut development. Trends Microbiol 12:129–134
Jaakkola JJK, Ahmed P, Ieromnimon A, Goepfert P, Laiou E, Quansah R, Jaakkola MS (2006) Preterm delivery and asthma: a systematic review and meta-analysis. J Allergy Clin Immunol 118:823–830
Kalliomaki M, Kirjavainen P, Eerola E, Kero P, Salminen S, Isolauri E (2001) Distinct patterns of neonatal gut microflora in infants in whom atopy was and was not developing. J Allergy Clin Immunol 107:129–134
Kastner U, Glasl S, Follrich B, Guggenbichler JP, Jurenitsch J (2002) Acid oligosaccharides as the active principle of aqueous carrot extracts for prevention and therapy of gastrointestinal infections. Wien Med Wochenschr 152:379–381
Kneepkens CM, Brand PL (2010) Clinical practice: breastfeeding and the prevention of allergy. Eur J Pediatr 169:911–917
Knol J, Boehm G, Lidestri M, Negretti F, Jelinek J, Agosti M, Stahl B, Marini A, Mosca F (2005) Increase of faecal bifidobacteria due to dietary oligosaccharides induces a reduction of clinically relevant pathogen germs in the faeces of formula-fed preterm infants. Acta Paediatr Suppl 94:31–33
Kvenshagen B, Jacobsen M, Halvorsen R (2009) Atopic dermatitis in premature and term children. Arch Dis Child 94:202–205
Lu L, Walker WA (2001) Pathologic and physiologic interactions of bacteria with the gastrointestinal epithelium. Am J Clin Nutr 73:1124S–1130S
Marra F, Lynd L, Coombes M, Richardson K, Legal M, Fitzgerald JM, Marra CA (2006) Does antibiotic exposure during infancy lead to development of asthma?: A systematic review and metaanalysis. Chest 129:610–618
Modi N, Uthaya S, Fell J, Kulinskaya E (2010) A randomised, double-blind, controlled trial of the effect of prebiotic oligosaccharides on enteral tolerance in preterm infants (ISRCTN77444690). Pediatr Res 68:440–445
Moro G, Arslanoglu S, Stahl B, Jelinek J, Wahn U, Boehm G (2006) A mixture of prebiotic oligosaccharides reduces the incidence of atopic dermatitis during the first six months of age. Arch Dis Child 91:814–819
Moro G, Minoli I, Mosca M, Fanaro S, Jelinek J, Stahl B, Boehm G (2002) Dosage-related bifidogenic effects of galacto- and fructooligosaccharides in formula-fed term infants. J Pediatr Gastroenterol Nutr 34:291–295
Ninonuevo MR, Lebrilla CB (2009) Mass spectrometric methods for analysis of oligosaccharides in human milk. Nutr Rev 67(Suppl 2):S216–S226
Odhiambo JA, Williams HC, Clayton TO, Robertson CF, Asher MI (2009) Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three. J Allergy Clin Immunol 124:1251–1258
Pearce N, Ait-Khaled N, Beasley R, Mallol J, Keil U, Mitchell E, Robertson C (2007) Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC). Thorax 62:758–766
Pelaia G, Vatrella A, Gallelli L, Renda T, Cazzola M, Maselli R, Marsico SA (2006) Respiratory infections and asthma. Respir Med 100:775–784
Penders J, Kummeling I, Thijs C (2011) Infant antibiotic use and wheeze and asthma risk—a systematic review and meta-analysis. Eur Respir J 38:295–302
Penders J, Thijs C, Vink C, Stelma FF, Snijders B, Kummeling I, van den Brandt PA, Stobberingh EE (2006) Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics 118:511–521
Rigo J, Pieltain C, Studzinski F, Knol J, Bindels JG (2001) Clinical evaluation in term infants of a new formula based on prebiotics, b-palmitate and hydrolysed proteins. J Pediatr Gastroenterol Nutr 32:402
Savino F, Roana J, Mandras N, Tarasco V, Locatelli E, Tullio V (2011) Faecal microbiota in breast-fed infants after antibiotic therapy. Acta Paediatr 100:75–78
Shreiner A, Huffnagle GB, Noverr MC (2008) The “microflora hypothesis” of allergic disease. Adv Exp Med Biol 635:113–134
Sjogren YM, Jenmalm MC, Bottcher MF, Bjorksten B, Sverremark-Ekstrom E (2009) Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 39:518–526
Spergel JM (2010) Epidemiology of atopic dermatitis and atopic march in children. Immunol Allergy Clin North Am 30:269–280
van den Berg A, van Zwol A, Moll HA, Fetter WPF, van Elburg RM (2007) Glutamine-enriched enteral nutrition in very low-birth-weight infants: effect on the incidence of allergic and infectious diseases in the first year of life. Arch Pediatr Adolesc Med 161:1095–1101
van der Velden VH, Laan MP, Baert MR, de Waal MR, Neijens HJ, Savelkoul HF (2001) Selective development of a strong Th2 cytokine profile in high-risk children who develop atopy: risk factors and regulatory role of IFN-gamma, IL-4 and IL-10. Clin Exp Allergy 31:997–1006
Van Zwol A, Van Den Berg A, Knol J, Twisk JWR, Fetter WPF, Van Elburg RM (2010) Intestinal microbiota in allergic and nonallergic 1-year-old very low birth weight infants after neonatal glutamine supplementation. Acta Paediatr 99:1868–1874
Vos AP, van Esch BC, Stahl B, M’Rabet L, Folkerts G, Nijkamp FP, Garssen J (2007) Dietary supplementation with specific oligosaccharide mixtures decreases parameters of allergic asthma in mice. Int Immunopharmacol 7:1582–1587
Westerbeek EA, van den Berg JP, Lafeber HN, Fetter WP, Boehm G, Twisk JW, van Elburg RM (2010) Neutral and acidic oligosaccharides in preterm infants: a randomized, double-blind, placebo-controlled trial. Am J Clin Nutr 91:679–686
Westerbeek EAM, van den Berg A, Lafeber HN, Knol J, Fetter WPF, van Elburg RM (2006) The intestinal bacterial colonisation in preterm infants: a review of the literature. Clin Nutr 25:361–368
Westerbeek EAM, van Elburg RM, van den Berg A, van den Berg J, Twisk JWR, Fetter WPF, Lafeber HN (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
Wickens K, Ingham T, Epton M, Pattemore P, Town I, Fishwick D, Crane J (2008) The association of early life exposure to antibiotics and the development of asthma, eczema and atopy in a birth cohort: confounding or causality? Clin Exp Allergy 38:1318–1324
Wills-Karp M, Santeliz J, Karp CL (2001) The germless theory of allergic disease: revisiting the hygiene hypothesis. Nat Rev Immunol 1:69–75
Acknowledgments
Study supplementation (prebiotic mixture and maltodextrin) and preterm formula (Nenatal Start) and postdicharge formula (Nenatal 1) for the study were provided by Danone Research, Friedrichsdorf, Germany. We are indebted to the parents for allowing their infants to participate in the study and for participating during the first year of life. Furthermore, we thank the medical and nursing staff of the NICU of the VU University Medical Center and all participating hospitals. The funding source was not involved in the analysis of the data nor the interpretation of the results.
Conflict of interest
RvE is also an employee of Danone Research. None of the authors had a financial relationship with the funding source.
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Niele, N., van Zwol, A., Westerbeek, E.A. et al. Effect of non-human neutral and acidic oligosaccharides on allergic and infectious diseases in preterm infants. Eur J Pediatr 172, 317–323 (2013). https://doi.org/10.1007/s00431-012-1886-2
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DOI: https://doi.org/10.1007/s00431-012-1886-2