title: Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys Randomized, Double-Blind, Placebo-Controlled Trial of Probiotics for Primary Prevention: No Clinical Effects of Lactobacillus GG Supplementation Probiotics during pregnancy and breast-feeding might confer immunomodulatory protection against atopic disease in the infant. World Allergy Organization-McMaster University Guidelines for Allergic Disease Prevention (GLAD-P): Probiotics Harms Reporting in Randomized Controlled Trials of Interventions Aimed at Modifying Microbiota
abstract: Perinatal administration of the probiotic Lactobacillus rhamnosus strain GG ( ATCC 53103 ) , reduces incidence of atopic eczema in at-risk children during the first 2 years of life ( infancy ) . We have therefore assessed persistence of the potential to prevent atopic eczema at 4 years . Atopic disease was diagnosed on the basis of a question naire and a clinical examination . 14 of 53 children receiving lactobacillus had developed atopic eczema , compared with 25 of 54 receiving placebo  ( relative risk 0.57 , 95 % CI 0.33 - 0.97 ) . Skin prick test reactivity was the same in both groups : ten of 50 children previously given lactobacillus compared with nine of 50 given placebo tested positive . Our results suggest that the preventive effect of lactobacillus GG on atopic eczema extends beyond infancy In this r and omized controlled trial , we examined the effect of early LGG infant supplementation in decreasing the risk of childhood eczema .  OBJECTIVES : To determine if probiotic administration during the first 6 months of life decreases  childhood asthma and eczema . METHODS : We conducted a r and omized , double-blind controlled trial of Lactobacillus rhamnosus GG ( LGG ) supplementation on the cumulative incidence of eczema ( primary end point ) and  asthma and rhinitis  ( secondary end points ) in high-risk infants . For the first 6 months of life , intervention infants ( n = 92 ) received a daily dose of 10 billion colony-forming units of LGG and 225 mg of inulin ( Amerifit Br and s , Cromwell , CT ) , and control infants ( n = 92 ) received 325 mg of inulin alone . We used survival analysis methods to estimate disease incidences in the presence or absence of LGG and to estimate the efficacy of LGG in delaying or preventing these diseases . RESULTS : Infants were accrued over a 6-year period ( median follow-up : 4.6 years ; 95 % retention rate at 2 years ) . At 2 years of age , the estimated cumulative incidence of eczema was 30.9 % ( 95 % confidence interval [ CI ] , 21.4%–40.4 % ) in the control arm and 28.7 % ( 95 % CI , 19.4%–38.0 % ) in the LGG arm , for a hazard ratio of 0.95 ( 95 % CI , 0.59–1.53 ) ( log-rank P = .83 ) . At 5 years of age , the cumulative incidence of asthma was 17.4 % ( 95 % CI , 7.6%–27.1 % ) in the control arm and 9.7 % ( 95 % CI , 2.7%–16.6 % ) in the LGG arm , for a hazard ratio of 0.88 ( 95 % CI , 0.41–1.87 ) ( log-rank P = .25 ) . CONCLUSIONS : For high-risk infants , early LGG supplementation for the first 6 months of life does not appear to prevent the development of eczema or asthma at 2 years of age To cite this article : Boyle RJ , Ismail IH , Kivivuori S , Licciardi PV , Robins‐Browne RM , Mah L‐J , Axelrad C , Moore S , Donath S , Carlin JB , Lahtinen SJ , Tang MLK . Lactobacillus GG treatment during pregnancy for the prevention of eczema  : a r and omized controlled trial . Allergy 2011 ; 66 : 509–516 BACKGROUND Data for trends in prevalence of asthma , allergic rhinoconjunctivitis , and eczema over time are scarce . We repeated the International Study of Asthma and Allergies in Childhood ( ISAAC ) at least 5 years after Phase One , to examine changes in the prevalence of symptoms of these disorders . METHODS For the ISAAC Phase Three study , between 2002 and 2003 , we did a  cross-sectional question naire survey of 193,404 children aged 6 - 7 years from 66 centres in 37 countries , and 304,679 children aged 13 - 14 years from 106 centres in 56 countries , chosen from a r and om sample of schools in a defined geographical area . FINDINGS Phase Three was completed a mean of 7 years after Phase One . Most centres showed a change in prevalence of 1 or more SE for at least one disorder , with increases being twice as common as decreases , and increases being more common in the 6 - 7 year age-group than in the 13 - 14 year age-group , and at most levels of mean prevalence . An exception was asthma symptoms in the older age-group , in which decreases were more common at high prevalence . For both age-groups , more centres showed increases in all three disorders more often than showing decreases , but most centres had mixed changes . INTERPRETATION The rise in prevalence of symptoms in many centres is concerning , but the absence of increases in prevalence of asthma symptoms for centres with existing high prevalence in the older age-group is reassuring . The divergent trends in prevalence of symptoms of allergic diseases form the basis for further research into the causes of such disorders BACKGROUND . The value of probiotics for primary prevention is controversial . Published trials vary considerably in study design and the applied probiotics , thereby limiting comparability of the results . OBJECTIVE . The purpose of this trial was to study the preventive effect of the probiotic Lactobacillus GG on the development of atopic dermatitis . METHODS . In a double-blind , placebo-controlled prospect i ve trial , 105 pregnant women from families with ≥1 member ( mother , father , or child ) with an atopic disease were r and omly assigned to receive either the probiotic Lactobacillus GG ( American Type Culture Collection 53103 ; 5 × 109 colony-forming units of Lactobacillus GG twice daily ) or placebo .  Ninety-four families ( 89.5 % ) completed the trial . The supplementation period started 4 to 6 weeks before expected delivery , followed by a postnatal period of 6 months . The primary end point was the occurrence of atopic dermatitis at the age of 2 years . Secondary outcomes were severity of atopic dermatitis , recurrent episodes of wheezing bronchitis , and allergic sensitization at the age of 2 years . RESULTS . Atopic dermatitis was diagnosed in 14 ( 28 % ) of 50 in the Lactobacillus GG group and in 12 ( 27.3 % ) of 44 in the placebo group . The risk of atopic dermatitis in children on probiotics relative to placebo was 0.96 ( confidence interval 0.38–2.33 ) . Severity of atopic dermatitis was comparable between the 2 groups . Notably , children with recurrent ( ≥5 ) episodes of wheezing bronchitis were more frequent in the Lactobacillus GG group ( 26 % ; n = 13 ) , as compared with the placebo group ( 9.1 % ; n = 4 ) . No difference was observed between both groups in total immunoglobulin E concentrations or numbers of specific sensitization to inhalant allergens . CONCLUSIONS . Supplementation with Lactobacillus GG during pregnancy and early infancy neither reduced the incidence of atopic dermatitis nor altered the severity of atopic dermatitis in affected children but was associated with an increased rate of recurrent episodes of wheezing bronchitis . Therefore , Lactobacillus GG can not be generally recommended for primary prevention The prevalence of atopic diseases is increasing throughout the Western world , and means of primary prevention are needed to reverse this trend . The role of breast-feeding , the best source of infant nutrition , in protection against atopic disease remains elusive . In this double-blinded , placebo-controlled study of 62 mother-infant pairs , it is shown that administering probiotics to the pregnant and lactating mother increased the immunoprotective potential of breast milk , as assessed by the amount of anti-inflammatory transforming growth factor beta2 ( TGF-beta2 ) in the milk ( 2885 pg/mL [ 95 % CI , 1624 - 4146 ] in mothers receiving probiotics vs 1340 pg/mL [ 95 % CI , 978 - 1702 ] in mothers receiving placebo ; P = .018 ) . The risk of developing atopic eczema during the first 2 years of life in infants whose mothers received  probiotics  was significantly reduced in comparison with that in infants whose mothers received placebo ( 15 % and 47 % , respectively ; relative risk , 0.32 [ 95 % CI , 0.12 - 0.85 ] ; P = .0098 ) .  Maternal atopy was a clear risk factor for atopic eczema in the infant . The infants most likely to benefit from maternal probiotic supplementation were those with an elevated cord blood IgE concentration . Administering probiotics during pregnancy and breast-feeding thus offers a safe and effective mode of promoting the immunoprotective potential of breast-feeding and provides protection against atopic eczema during the first 2 years of life Background Prevalence of  allergic diseases in infants , whose parents and siblings do not have allergy , is approximately 10 % and reaches 20–30 % in those with an allergic first-degree relative . Intestinal microbiota may modulate immunologic and inflammatory systemic responses and , thus , influence development of sensitization and allergy . Probiotics have been reported to modulate immune responses and their supplementation has been proposed as a preventive intervention . Objective The World Allergy Organization ( WAO ) convened a guideline panel to develop evidence -based recommendations about the use of probiotics in the prevention of allergy . Methods We identified the most relevant clinical questions and performed a systematic review of r and omized controlled trials of probiotics for the prevention of allergy . We followed the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) approach to develop recommendations . We search ed for and review ed the evidence about health effects , patient values and preferences , and re source use ( up to November 2014 ) . We followed the GRADE evidence -to-decision framework to develop recommendations . Results Currently available evidence does not indicate that probiotic supplementation  reduces the risk of developing allergy in children . However , considering all critical outcomes in this context , the WAO guideline panel determined that there is a likely net benefit from using probiotics result ing primarily from prevention of eczema . The WAO guideline panel suggests : a ) using probiotics in pregnant women at high risk for having an allergic child ; b ) using probiotics in women who breastfeed infants at high risk of developing allergy ; and c ) using probiotics in infants at high risk of developing allergy . All recommendations are conditional and supported by very low quality evidence . Conclusions WAO recommendations about probiotic supplementation for prevention of allergy are intended to support parents , clinicians and other health care professionals in their decisions whether to use probiotics in pregnancy and during breastfeeding , and whether to give them to infants IN RESPONSE : We agree with Dr. Baldassarre that the regulatory model for approval of probiotics , prebiotics , and synbiotics could alter the evaluation of adverse events in r and omized controlled trials , which may cause study publications to omit some safety data . This regulatory model has remained ambiguous and complex and varies by region ( 1 , 2 ) . Probiotics that have a long historical use or are used as additives or processing aids have been subject to few or no regulations . In contrast , those intended for new therapeutic purpose s must follow a strict process for approval ( 3 ) . We recognize that the safety and efficacy findings associated with a specific probiotic formulation should not be generalized to a new formulation . Knowing the precise identity of a probiotic that was assessed in a r and omized controlled trial is fundamental to determine its exact safety profile . The identification methods typically used ( such as pulsed-field gel electrophoresis and r and omly amplified polymorphic DNA analysis ) allow for differentiation of individual strains but are otherwise inadequate for species recognition ( 2 ) . Inconsistencies in the bacterial identification for probiotics may lead to a biased safety profile and erroneous decision making and have major consequences for patients . It is crucial that toxicology of these products take into account the dose , formulation , bacterial species , and target population . That all stakeholdersincluding laboratories , government regulatory authorities , and scientistsbe prepared to address this important topic is critical . Nevertheless , problems with the regulatory model can not fully explain why 28 % of trials did not report any information on harms and 70 % inadequately reported harms-related data . Poor reporting of harms may be due to distorted reporting of adverse events in the trials , silencing the evidence on harms , or lack of knowledge on how to report adverse events in publications ( 4 ) . Inadequate reporting of adverse events in published articles of r and omized controlled trials remains a major problem in several medical areas . We need to promote more active implementation and endorsement of recommendations for st and ardizing the evaluation of these interventions and reporting harms-related data . The points raised by Dr. Baldassarre and the findings of our study highlight that a collective , international effort is urgently needed to improve the evaluation of these products
target: High to moderate certainty in the body of evidence suggests that LGG supplementation ( regardless of the timing of administration ) did not reduce the risk of eczema .
  There was also no consistent effect on other allergic outcomes .
  This meta- analysis shows that LGG was ineffective in reducing eczema .
background: Current guidelines recommend the use of probiotics to reduce the risk of  eczema .
  It remains unclear which strain(s ) to use .
  We systematic ally evaluated data on the efficacy of Lactobacillus rhamnosus GG ( LGG ) supplementation prenatally and /or postnatally for the primary prevention of eczema .