Clinical trial NCT01285830: Primary Prevention of Allergic Disease in Early Child by Lactobacillus Reuteri
Official title: Primary Prevention of Allergic Disease in Early Child by Lactobacillus Reuteri
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Allergic Conditions
Keywords: Infants
Probiotics
Prevention
Lactobacillus reuteri
Eczema
IgE
Sensitization
Microbiota
Chemokines
Lead sponsor: Linkoeping University
Sponsor class: OTHER_GOV
Collaborators: name: BioGaia AB
name: The Ekhaga Foundation, Sweden
name: The Heart and Lung foundation, Sweden
name: The Research Council for the South-East Sweden
name: The Swedish Asthma and Allergy Association, Sweden
name: The Swedish Research Council
name: University Hospital, Linkoeping
First posted: 2011-01-28
Enrollment: 232
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: An altered microbial exposure may be partly responsible for the increase of allergic diseases in populations with a western lifestyle. Activation of the immune system by microbes early in life is probably required for an accurate maturation of the immune system. Probiotics, live bacteria which are considered to confer health when ingested, have been suggested to prevent eczema and sensitisation infants.

The aim of this study is to assess the effect of oral supplementation with the probiotic bacterium Lactobacillus reuteri in infancy on the development of allergic disease and sensitisation during the first 2 years of life and to examine mechanisms possibly underlying eventual effects on allergic manifestations.

A follow up was performed at 7 years of age.

Detailed description: An altered microbial exposure may be partly responsible for the increase of allergic diseases in populations with a western lifestyle. Activation of the immune system by microbes early in life is probably required for an accurate maturation of the immune system. Probiotics, live bacteria which are considered to confer health when ingested, have been suggested to prevent eczema and sensitisation infants.

The aim of this study is to assess the effect of oral supplementation with the probiotic bacterium Lactobacillus reuteri (L. reuteri) in infancy on the development of allergic disease and sensitisation during the first 2 years of life and to examine mechanisms possibly underlying eventual effects on allergic manifestations. In the study the development of allergic disease will also be related prospectively to immunological, nutritional and environmental factors.

The study is a prospective double-blind placebo-controlled multicenter trial, comprising 232 families with allergic disease. The families are recruited at the antenatal clinic, and the mothers will receive L. reuteri ATCC 55730 (1 x 100 000 000 colony forming units, Biogaia AB, Stockholm, Sweden) or placebo daily from gestational week 36 until delivery. Their babies then will continue with the same study product from birth until 12 months of age and will be followed up for another year. Clinical follow-up will be done at 1, 3, 6,12 and 24 months of age and telephone interviews at 2,4,5, 8, 10 and 18 months. A questionnaire will be completed on each occasion. Skin prick test will be performed at 6, 12 and 24 months of age. Venous blood will be collected from the umbilical cord and at 6, 12 and 24 months and stored as heparinized plasma or serum until assessment. Peripheral mononuclear blood cells (PBMC) will be separated from the plasma samples before storage. Blood samples will also be collected from the mother and father once during the study. The stool sample will be collected from the mother during the 1 week after delivery and the infant at 5-7 days, 1 month, 3 months, 6 months, 12 months and 24 months of age. Saliva samples will be collected at 3, 6, 12 and 24 months of age and breast milk samples will be collected from the mother 1-3 days and 1 months after delivery. The saliva, breast milk and plasma/serum samples will be stored in -20°C and stool samples and the PBMC in -70°C until assessment.

A follow up was performed at 7 years of age focusing on allergic disease. Spirometry, skin prick test was performed. Of the 188 completing the 2 year follow up, 184 also completed the 7 year follow up.

Eligibility criteria: Inclusion Criteria:

* Pregnant women with history of previous or present allergic disease in at least one member of the immediate family (parents or siblings).
* Expected compliance.
* Written informed consent obtained from parents.

Exclusion Criteria:

* Insufficient compliance, i.e. a consumption of the study product below half of the expected.

Primary outcomes:
measure: Allergic disease
timeFrame: Incidence until 2 years of age
Secondary outcomes:
measure: Sensitization
timeFrame: incidence until 2 years of age
measure: IgE-associated allergic disease
timeFrame: Incidence until 2 years of age
measure: Lactobacillus reuteri colonization in stool and breast milk
timeFrame: Point prevalance until 2 years of age
measure: Cytokines in breast milk
timeFrame: 1-3 days and 1 months postpartum
measure: Th1 and Th2- associated chemokines in blood samples
timeFrame: Development from birth until 2 years of age
measure: Microbial composition in stool samples
timeFrame: Development from birth until 2 years of age
measure: Allergic disease at 7 years of age
timeFrame: 2001-2011
measure: Prevalence of caries in primary dentition at 8 years of age
timeFrame: 2009-2012
Other outcomes:
Locations:
city: Jönköping
country: Sweden
facility: Pediatric Clinic, Ryhov Hospital
city: Linköping
country: Sweden
facility: Pediatric Clinic, University Hospital
city: Norrköping
country: Sweden
facility: Pediatric Clinic, Vrinnevi Hospital
Study officials:
affiliation: The National Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
name: Bengt Björkstén, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Abrahamsson TR, Jakobsson T, Bottcher MF, Fredrikson M, Jenmalm MC, Bjorksten B, Oldaeus G. Probiotics in prevention of IgE-associated eczema: a double-blind, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2007 May;119(5):1174-80. doi: 10.1016/j.jaci.2007.01.007. Epub 2007 Mar 8.
citation: Bottcher MF, Abrahamsson TR, Fredriksson M, Jakobsson T, Bjorksten B. Low breast milk TGF-beta2 is induced by Lactobacillus reuteri supplementation and associates with reduced risk of sensitization during infancy. Pediatr Allergy Immunol. 2008 Sep;19(6):497-504. doi: 10.1111/j.1399-3038.2007.00687.x. Epub 2008 Jan 22.
citation: Abrahamsson TR, Sinkiewicz G, Jakobsson T, Fredrikson M, Bjorksten B. Probiotic lactobacilli in breast milk and infant stool in relation to oral intake during the first year of life. J Pediatr Gastroenterol Nutr. 2009 Sep;49(3):349-54. doi: 10.1097/MPG.0b013e31818f091b.
citation: Connolly E, Abrahamsson T, Bjorksten B. Safety of D(-)-lactic acid producing bacteria in the human infant. J Pediatr Gastroenterol Nutr. 2005 Oct;41(4):489-92. doi: 10.1097/01.mpg.0000176179.81638.45. No abstract available.
citation: Abrahamsson TR, Sandberg Abelius M, Forsberg A, Bjorksten B, Jenmalm MC. A Th1/Th2-associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization. Clin Exp Allergy. 2011 Dec;41(12):1729-39. doi: 10.1111/j.1365-2222.2011.03827.x. Epub 2011 Aug 1.
citation: Abrahamsson TR, Jakobsson HE, Andersson AF, Bjorksten B, Engstrand L, Jenmalm MC. Low diversity of the gut microbiota in infants with atopic eczema. J Allergy Clin Immunol. 2012 Feb;129(2):434-40, 440.e1-2. doi: 10.1016/j.jaci.2011.10.025. Epub 2011 Dec 6.
citation: Forsberg A, Abrahamsson TR, Bjorksten B, Jenmalm MC. Pre- and post-natal Lactobacillus reuteri supplementation decreases allergen responsiveness in infancy. Clin Exp Allergy. 2013 Apr;43(4):434-42. doi: 10.1111/cea.12082.
citation: Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, Bjorksten B, Engstrand L, Andersson AF. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut. 2014 Apr;63(4):559-66. doi: 10.1136/gutjnl-2012-303249. Epub 2013 Aug 7.
citation: Abrahamsson TR, Jakobsson T, Bjorksten B, Oldaeus G, Jenmalm MC. No effect of probiotics on respiratory allergies: a seven-year follow-up of a randomized controlled trial in infancy. Pediatr Allergy Immunol. 2013 Sep;24(6):556-61. doi: 10.1111/pai.12104. Epub 2013 Jul 31.
citation: Abrahamsson TR, Jakobsson HE, Andersson AF, Bjorksten B, Engstrand L, Jenmalm MC. Low gut microbiota diversity in early infancy precedes asthma at school age. Clin Exp Allergy. 2014 Jun;44(6):842-50. doi: 10.1111/cea.12253.
citation: Forsberg A, Abrahamsson TR, Bjorksten B, Jenmalm MC. Pre- and postnatal administration of Lactobacillus reuteri decreases TLR2 responses in infants. Clin Transl Allergy. 2014 Jun 25;4:21. doi: 10.1186/2045-7022-4-21. eCollection 2014.
citation: Abrahamsson TR, Rautava S, Moore AM, Neu J, Sherman PM. The time for a confirmative necrotizing enterocolitis probiotics prevention trial in the extremely low birth weight infant in North America is now! J Pediatr. 2014 Aug;165(2):389-94. doi: 10.1016/j.jpeds.2014.05.012. Epub 2014 Jun 16. No abstract available.