Treating infant colic with the probiotic Lactobacillus reuteri: double blind, placebo controlled randomised trial

Valerie Sung, Harriet Hiscock, Mimi L K Tang, Fiona K Mensah, Monica L Nation, Catherine Satzke, Ralf G Heine, Amanda Stock, Ronald G Barr, Melissa Wake, Valerie Sung, Harriet Hiscock, Mimi L K Tang, Fiona K Mensah, Monica L Nation, Catherine Satzke, Ralf G Heine, Amanda Stock, Ronald G Barr, Melissa Wake

Abstract

Objective: To determine whether the probiotic Lactobacillus reuteri DSM 17938 reduces crying or fussing in a broad community based sample of breastfed infants and formula fed infants with colic aged less than 3 months.

Design: Double blind, placebo controlled randomised trial.

Setting: Community based sample (primary and secondary level care centres) in Melbourne, Australia.

Participants: 167 breastfed infants or formula fed infants aged less than 3 months meeting Wessel's criteria for crying or fussing: 85 were randomised to receive probiotic and 82 to receive placebo.

Interventions: Oral daily L reuteri (1 × 10(8) colony forming units) versus placebo for one month.

Main outcomes measures: The primary outcome was daily duration of cry or fuss at 1 month. Secondary outcomes were duration of cry or fuss; number of cry or fuss episodes; sleep duration of infant at 7, 14, and 21 days, and 1 and 6 months; maternal mental health (Edinburgh postnatal depression subscale); family functioning (paediatric quality of life inventory), parent quality adjusted life years (assessment of quality of life) at 1 and 6 months; infant functioning (paediatric quality of life inventory) at 6 months; infant faecal microbiota (microbial diversity, colonisation with Escherichia coli), and calprotectin levels at 1 month. In intention to treat analyses the two groups were compared using regression models adjusted for potential confounders.

Results: Of 167 infants randomised from August 2011 to August 2012, 127 (76%) were retained to primary outcome; of these, a subset was analysed for faecal microbial diversity, E coli colonisation, and calprotectin levels. Adherence was high. Mean daily cry or fuss time fell steadily in both groups. At 1 month, the probiotic group cried or fussed 49 minutes more than the placebo group (95% confidence interval 8 to 90 minutes, P=0.02); this mainly reflected more fussing, especially for formula fed infants. The groups were similar on all secondary outcomes. No study related adverse events occurred.

Conclusions: L reuteri DSM 17938 did not benefit a community sample of breastfed infants and formula fed infants with colic. These findings differ from previous smaller trials of selected populations and do not support a general recommendation for the use of probiotics to treat colic in infants.

Trial registration: Current Controlled Trials ISRCTN95287767.

Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare that: VS, HH, FM, and MW have support from the Australian National Health and Medical Research Council for the submitted work; RB is supported by a Canada research chair in community child health research and by the Child and Family Research Institute of BC Children’s Hospital; MT is a member of the Nestlé Nutrition Institute Medical Advisory Board Oceania and the Nutricia Medical Advisory Board Australasia, received honorariums for speaking at symposiums sponsored by Nestlé Nutrition Institute and Nutricia (Danone), and received probiotic and placebo research products from Nestlé Research Centre Switzerland and Dicofarm Italy for studies unrelated to this trial; RH is a member of the Nestlé Nutrition Institute Medical Advisory Board Oceania and the Nutricia Medical Advisory Board Australasia and received honorariums for speaking at symposiums sponsored by Nestlé Nutrition Institute and Nutricia (Danone); the authors’ spouses, partners, or children have no financial relationships that may be relevant to the submitted work; and the authors have no other relationships or activities that could appear to have influenced the submitted work.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793609/bin/sunv015994.f1_default.jpg
Fig 1 Participant flow through study
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793609/bin/sunv015994.f2_default.jpg
Fig 2 Daily duration of cry or fuss over study period and at 6 month follow-up. Day 28=1 month; day 183=6 months
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793609/bin/sunv015994.f3_default.jpg
Fig 3 Meta-analysis of previous randomised controlled trials of probiotics for management of infant colic (outcomes at 21 days post-intervention)
https://www.ncbi.nlm.nih.gov/pmc/articles/instance/4793609/bin/sunv015994.f4_default.jpg
Fig 4 Meta-analysis of previous randomised controlled trials of probiotics for management of infant colic with addition of results from this study

References

    1. Wake M, Morton-Allen E, Poulakis Z, Hiscock H, Gallagher S, Oberklaid F. Prevalence, stability, and outcomes of cry-fuss and sleep problems in the first 2 years of life: prospective community-based study. Pediatrics 2006;117:836-42.
    1. Wessel MA, Cobb JC, Jackson EB, Harris GS, Detwiler AC. Paroxysmal fussing in infancy, sometimes called “colic.” Pediatrics 1954;14:421-34.
    1. McMahon C, Barnett B, Kowalenko N, Tennant C, Don N. Postnatal depression, anxiety and unsettled infant behaviour. Aust N Z J Psychiatry 2001;35:581-8.
    1. Howard CR, Lanphear N, Lanphear BP, Eberly S, Lawrence RA. Parental responses to infant crying and colic: the effect on breastfeeding duration. Breastfeed Med 2006;1:146-55.
    1. Barr RG. Preventing abusive head trauma resulting from a failure of normal interaction between infants and their caregivers. Proc Natl Acad Sci USA 2012;109(Suppl 2):17294-301.
    1. Morris S, James-Roberts IS, Sleep J, Gillham P. Economic evaluation of strategies for managing crying and sleeping problems. Arch Dis Childhood 2001;84:15-9.
    1. Barr RG. Excessive crying. In: Sameroff AJ, Lewis M, Miller SM, eds. Handbook of developmental psychopathology. Kluwer Academic/Plenum Press, 2000:327-50.
    1. Rhoads JM, Fatheree NY, Norori J, Liu Y, Lucke JF, Tyson JE, et al. Altered fecal microflora and increased fecal calprotectin in infants with colic. J Pediatr 2009;155:823-8.e1.
    1. Olafsdottir E, Aksnes L, Fluge G, Berstad A. Faecal calprotectin levels in infants with infantile colic, healthy infants, children with inflammatory bowel disease, children with recurrent abdominal pain and healthy children. Acta Paediatr 2002;91:45-50.
    1. Cohen-Silver J, Ratnapalan S. Management of infantile colic: a review. Clin Pediatr 2009;48:14-7.
    1. Garrison MM, Christakis DA. A systematic review of treatments for infant colic.[see comment]. Pediatrics 2000;106:184-90.
    1. Lucassen PL, Assendelft WJ. Systematic review of treatments for infant colic. Pediatrics 2001;108:1047-8.
    1. National Institute for Health and Care Excellence guidelines. Colic—infantile. Clinical knowledge summaries. 2014. .
    1. Heine RG. Cow’s milk allergy and lactose malabsorption in infants with colic. J Pediatr Gastroenterol Nutr 2013;57(Suppl 1):25-7.
    1. Ghosh S, Barr RG. Colic and gas. In: Walker W, Goulet O, Kleinman R, Sherman P, Shneider B, Sanderson I, eds. Pediatric gastrointestinal disease. BC Decker, 2004:210-24.
    1. Weissbluth M, Christoffel KK, Davis AT. Treatment of infantile colic with dicyclomine hydrochloride. J Pediatr 1984;104:951-5.
    1. Illingworth RS. Evening colic in infants: a double-blind trial of dicyclomine hydrochloride. Lancet 1959;2:1119-20.
    1. Grunseit F. Evaluation of the efficacy of dicyclomine hydrochloride (‘Merbentyl’) syrup in the treatment of infant colic. Curr Med Res Opin 1977;5:258-61.
    1. Williams J, Watkins-Jones R. Dicyclomine: worrying symptoms associated with its use in some small babies. BMJ 1984;288:901.
    1. De Weerth C, Fuentes S, Puylaert P, de Vos WM. Intestinal microbiota of infants with colic: development and specific signatures. Pediatrics 2013;131:e550-8.
    1. Savino F, Cordisco L, Tarasco V, Calabrese R, Palumeri E, Matteuzzi D. Molecular identification of coliform bacteria from colicky breastfed infants. Acta Paediatr 2009;98:1582-8.
    1. Savino F, Cresi F, Pautasso S, Palumeri E, Tullio V, Roana J, et al. Intestinal microflora in breastfed colicky and non-colicky infants. Acta Paediatr 2004;93:825-9.
    1. Partty A, Kalliomaki M, Endo A, Salminen S, Isolauri E. Compositional development of Bifidobacterium and Lactobacillus microbiota is linked with crying and fussing in early infancy. PLoS One 2012;7.
    1. Penna FJ, Peret LA, Vieira LQ, Nicoli JR. Probiotics and mucosal barrier in children. Curr Opin Clin Nutr Metab Care 2008;11:640-4.
    1. Grzeskowiak L, Gronlund MM, Beckmann C, Salminen S, von Berg A, Isolauri E. The impact of perinatal probiotic intervention on gut microbiota: double-blind placebo-controlled trials in Finland and Germany. Anaerobe 2012;18:7-13.
    1. Duchmann R. The role of probiotics and antibiotics in regulating mucosal inflammation. Adv Exp Med Biol 2006;579:219-26.
    1. Lutgendorff F, Akkermans LM, Soderholm JD. The role of microbiota and probiotics in stress-induced gastro-intestinal damage. Curr Mol Med 2008;8:282-98.
    1. Mohan R, Koebnick C, Schildt J, Schmidt S, Mueller M, Possner M, et al. Effects of Bifidobacterium lactis Bb12 supplementation on intestinal microbiota of preterm infants: a double-blind, placebo-controlled, randomized study. J Clin Microbiol 2006;44:4025-31.
    1. Mentula S, Tuure T, Koskenala R, Korpela R, Kononen E. Microbial composition and fecal fermentation end products from colicky infants—a probiotic supplementation pilot. Microb Ecol Health Dis 2008;20:37-47.
    1. Savino F, Cordisco L, Tarasco V, Locatelli E, Di Gioia D, Oggero R, et al. Antagonistic effect of Lactobacillus strains against gas-producing coliforms isolated from colicky infants. BMC Microbiol 2011;11:157.
    1. Sung V, Collett S, De Gooyer T, Hiscock H, Tang ML, Wake M. Probiotics to prevent or treat excessive infant crying: Systematic review and meta-analysis. JAMA Pediatrics 2013;167:1150-7.
    1. Savino F, Pelle E, Palumeri E, Oggero R, Miniero R. Lactobacillus reuteri (American type culture collection strain 55730) versus simethicone in the treatment of infantile colic: a prospective randomized study. Pediatrics 2007;119:e124-30.
    1. Savino F, Cordisco L, Tarasco V, Palumeri E, Calabrese R, Oggero R, et al. Lactobacillus reuteri DSM 17 938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics 2010;126:e526-33.
    1. Sung V, Hiscock H, Tang ML, Mensah FK, Heine RG, Stock A, et al. Probiotics to improve outcomes of colic in the community: protocol for the Baby Biotics randomised controlled trial. BMC Pediatr 2012;12:135.
    1. Barr RG, Kramer MS, Leduc DG, Boisjoly C, McVey-White L, Pless IB. Parental diary of infant cry and fuss behavior. Arch Dis Child 1988;63:380-7.
    1. Szajewska H, Gyrczuk E, Horvath A. Lactobacillus reuteri DSM 17938 for the management of infantile colic in breastfed infants: a randomized, double-blind, placebo-controlled trial. J Pediatr 2013;162:257-62.
    1. Cox JL, Holden JM, Sagovski R. Detection of postnatal depression: development of a 10-item Edinburgh postnatal depression scale. Br J Psychiatry 1987;150:1172-5.
    1. Varni JW, Limbers CA, Nieighbors K, Schulz K, Lieu JEC, Heffer RW, et al. The PedsQL infant scales: feasibility, internal consistency, reliability, and validity in healthy and ill infants. Qual Life Res 2010; published online 22 Aug. .
    1. Varni JW, Sherman SA, Burwinkle TM, Dickinson PE, Dixon P. The PedsQLTM family impact module: preliminary reliability and validity. Health Qual Life Outcomes 2004;2:55.
    1. Hawthorne G, Richardson J, Atherton Day M. A comparison of the Assessment of Quality of Life (AQoL) with four other generic utility instruments. Ann Med 2001;33:358-70.
    1. Osborne CA, Rees GN, Bernstein Y, Janssen PH. New threshold and confidence estimates for terminal restriction fragment length polymorphism analysis of complex bacterial communities. Appl Environ Microbiol 2006;72:1270-8.
    1. Chern EC, Siefring S, Paar J, Doolittle M, Haugland RA. Comparison of quantitative PCR assays for Escherichia coli targeting ribosomal RNA and single copy genes. Lett Appl Microbiol 2011;52:298-306.
    1. CALPRO. CalproLab ELISA kit. 2012. .
    1. Ouwehand AC, Isolauri E, He F, Hashimoto H, Benno Y, Salminen S. Differences in Bifidobacterium flora composition in allergic and healthy infants. J Allergy Clin Immunol 2001;108:144-5.
    1. Stsepetova J, Sepp E, Julge K, Vaughan E, Mikelsaar M, de Vos WM. Molecularly assessed shifts of Bifidobacterium ssp and less diverse microbial communities are characteristic of 5-year-old allergic children. FEMS Immunol Med Microbiol 2007;51:260-9.
    1. Songjinda P, Nakayama J, Tateyama A, Tanaka S, Tsubouchi M, Kiyohara C, et al. Differences in developing intestinal microbiota between allergic and non-allergic infants: a pilot study in Japan. Biosci Biotechnol Biochem 2007;71:2338-42.
    1. Suzuki S, Shimojo N, Tajiri Y, Kumemura M, Kohno Y. Differences in the composition of intestinal Bifidobacterium species and the development of allergic diseases in infants in rural Japan. Clin Exp Allergy 2007;37:506-11.
    1. Gore C, Munro K, Lay C, Bibiloni R, Morris J, Woodcock A, et al. Bifidobacterium pseudocatenulatum is associated with atopic eczema: a nested case-control study investigating the fecal microbiota of infants. J Allergy Clin Immunol 2008;121:135-40.
    1. Osborne NJ, Koplin JJ, Martin PE, Gurrin LC, Thiele L, Tang ML, et al. The HealthNuts population-based study of paediatric food allergy: validity, safety and acceptability. Clin Exp Allergy 2010;40:1516-22.
    1. Moore DJ, Tao BS, Lines DR, Hirte C, Heddle ML, Davidson GP. Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux. J Pediatr 2003;143:219-23.
    1. Jordan B, Heine RG, Meehan M, Catto-Smith AG, Lubitz L. Effect of antireflux medication, placebo and infant mental health intervention on persistent crying: a randomized clinical trial. J Paediatr Child Health 2006;42:49-58.
    1. St James-Roberts I, Alvarez M, Csipke E, Abramsky T, Goodwin J, Sorgenfrei E. Infant crying and sleeping in London, Copenhagen and when parents adopt a “proximal” form of care. Pediatrics 2006;117:e1146-55.
    1. St James-Roberts I, Hurry J, Bowyer J, Barr RG. Supplementary carrying compared with advice to increase responsive parenting as interventions to prevent persistent infant crying. Pediatrics 1995;95:381-8.
    1. Barr RG, McMullan SJ, Spiess H, Leduc DG, Yaremko J, Barfield R, et al. Carrying as colic “therapy”: a randomized controlled trial. Pediatrics 1991;87:623-30.
    1. MetaregisterOfControlledTrials. Registered trials numbers ISRCTN95287767, NCT01067027, NCT01279265, NCT01541046, NCT01017991. 2012. .

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться