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To the Editor:We appreciate the critical commentary1Salfeld P. Kopp M.V. Probiotics cannot be generally recommended for primary prevention of atopic dermatitis.J Allergy Clin Immunology. 2009; 124: 170Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar on our meta-analysis of prevention and treatment trials of probiotics for atopic dermatitis (AD).2Lee J. Seto D. Bielory L. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis.J Allergy Clin Immunol. 2008; 121: 116-121Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar Indeed, there are many yet-to-be determined variables in probiotics' effects. As suggested by the recent observations by Kuitunen et al,3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar probiotics may be of greater benefit for infants who are delivered by C-section. It will be interesting to see if this is observed in other studies.Boyle4Boyle R. Probiotics for the treatment or prevention of atopic eczema.J Allergy Clin Immunol. 2009; 123 ([letter]): 266-267Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar also raised the issue of overlapping participant pools of the Kalliomaki and Rautava studies, and we attributed this to the lack of cues in reporting. Our inclusion of Kalliomaki et al's 4-year follow-up data was intentional because it provided an extended look at the outcome of interest. In our response to Boyle, recalculations after excluding these 2 trials did not change the statistical significance.5Lee J. Bielory L. Reply.J Allergy Clin Immunol. 2009; 123: 267Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Our analysis only included trials with prenatal supplementation, with the intent of minimizing methodological variations, which is why we initially excluded the Taylor et al study.6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google ScholarTo be fair, we recalculated the prevention studies summary effect size with the addition of the Taylor et al6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar and Kopp et al7Kopp M.V. Hennemuth I. Dietschek A. Goldstein M. Ihorst G. Heinzmann A. et al.A randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical or immunological effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-e856Crossref PubMed Scopus (344) Google Scholar studies (n = 1511), which resulted in a more conservative but still statistically significant fixed relative risk of 0.76 (95% CI; 0.62-0.92). In this pooling the Kukkonen et al8Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar study had an even greater weight of 45.39% based on population size. Excluding this study altogether reduced the fixed relative risk further to 0.81 (0.63-1.03; n = 589), rendering the summary effect size statistically insignificant.All these permutations in pooling have significant statistical heterogeneity, which is not surprising given the variations in study design among the prevention trials. Indeed, the positive study of Kukkonen et al,8Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar unlike the other 4 prevention studies, used a prebiotic in addition to probiotics. Perhaps our attempts to minimize methodological variation were in vain. However, timing does seem to affect the observed outcome. Taylor et al6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar did not supplement the mothers and assessed the incidence of AD at 6 months as opposed to at 2 years, as done by the other 4 prevention studies. Timing the importance of the timing of end point assessment is highlighted by the loss of observed differences in frequencies of eczema (39.3% vs 43.3%) and AD (24.0% vs 25.1%) in 891 (88%) of the 1018 infants from the Kuitunen et al3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar trial at 5 years out from intervention.More recent trials have detected an increased incidence of recurrent wheezing and allergic sensitization among infants given 2 different strains of Lactobacillus species, including 1 used in the Kalliomaki et al study.6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 7Kopp M.V. Hennemuth I. Dietschek A. Goldstein M. Ihorst G. Heinzmann A. et al.A randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical or immunological effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-e856Crossref PubMed Scopus (344) Google Scholar In contrast, among infants from the Kuitunen et al3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar study, similar frequencies of allergic rhinitis (20.7% vs 19.1%) and asthma (13.0% vs 14.1%) were observed 5 years out from intervention. This makes the case for ongoing and future prevention trials to consider evaluating the frequency of allergic respiratory disease at multiple time points over a longer period of time.We do agree with Salfeld and Kopp1Salfeld P. Kopp M.V. Probiotics cannot be generally recommended for primary prevention of atopic dermatitis.J Allergy Clin Immunology. 2009; 124: 170Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar that probiotics should not be considered a universal recommendation for pregnant women with atopic histories. It will be interesting to see if other studies demonstrate a greater therapeutic potential for probiotics for infants born to at-risk women via cesarean deliveries. To the Editor: We appreciate the critical commentary1Salfeld P. Kopp M.V. Probiotics cannot be generally recommended for primary prevention of atopic dermatitis.J Allergy Clin Immunology. 2009; 124: 170Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar on our meta-analysis of prevention and treatment trials of probiotics for atopic dermatitis (AD).2Lee J. Seto D. Bielory L. Meta-analysis of clinical trials of probiotics for prevention and treatment of pediatric atopic dermatitis.J Allergy Clin Immunol. 2008; 121: 116-121Abstract Full Text Full Text PDF PubMed Scopus (303) Google Scholar Indeed, there are many yet-to-be determined variables in probiotics' effects. As suggested by the recent observations by Kuitunen et al,3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar probiotics may be of greater benefit for infants who are delivered by C-section. It will be interesting to see if this is observed in other studies. Boyle4Boyle R. Probiotics for the treatment or prevention of atopic eczema.J Allergy Clin Immunol. 2009; 123 ([letter]): 266-267Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar also raised the issue of overlapping participant pools of the Kalliomaki and Rautava studies, and we attributed this to the lack of cues in reporting. Our inclusion of Kalliomaki et al's 4-year follow-up data was intentional because it provided an extended look at the outcome of interest. In our response to Boyle, recalculations after excluding these 2 trials did not change the statistical significance.5Lee J. Bielory L. Reply.J Allergy Clin Immunol. 2009; 123: 267Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Our analysis only included trials with prenatal supplementation, with the intent of minimizing methodological variations, which is why we initially excluded the Taylor et al study.6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar To be fair, we recalculated the prevention studies summary effect size with the addition of the Taylor et al6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar and Kopp et al7Kopp M.V. Hennemuth I. Dietschek A. Goldstein M. Ihorst G. Heinzmann A. et al.A randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical or immunological effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-e856Crossref PubMed Scopus (344) Google Scholar studies (n = 1511), which resulted in a more conservative but still statistically significant fixed relative risk of 0.76 (95% CI; 0.62-0.92). In this pooling the Kukkonen et al8Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar study had an even greater weight of 45.39% based on population size. Excluding this study altogether reduced the fixed relative risk further to 0.81 (0.63-1.03; n = 589), rendering the summary effect size statistically insignificant. All these permutations in pooling have significant statistical heterogeneity, which is not surprising given the variations in study design among the prevention trials. Indeed, the positive study of Kukkonen et al,8Kukkonen K. Savilahti E. Haahtela T. Juntunen-Backman K. Korpela R. Poussa T. et al.Probiotics and prebiotic galacto-oligosaccharides in the prevention of allergic diseases: a randomized, double-blind, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 192-198Abstract Full Text Full Text PDF PubMed Scopus (576) Google Scholar unlike the other 4 prevention studies, used a prebiotic in addition to probiotics. Perhaps our attempts to minimize methodological variation were in vain. However, timing does seem to affect the observed outcome. Taylor et al6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar did not supplement the mothers and assessed the incidence of AD at 6 months as opposed to at 2 years, as done by the other 4 prevention studies. Timing the importance of the timing of end point assessment is highlighted by the loss of observed differences in frequencies of eczema (39.3% vs 43.3%) and AD (24.0% vs 25.1%) in 891 (88%) of the 1018 infants from the Kuitunen et al3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar trial at 5 years out from intervention. More recent trials have detected an increased incidence of recurrent wheezing and allergic sensitization among infants given 2 different strains of Lactobacillus species, including 1 used in the Kalliomaki et al study.6Taylor A.L. Dunstan J.A. Prescott S.L. Probiotic supplementation for the first 6 months of life fails to reduce the risk of atopic dermatitis and increases the risk of allergen sensitization in high-risk children: a randomized controlled trial.J Allergy Clin Immunol. 2007; 119: 184-191Abstract Full Text Full Text PDF PubMed Scopus (427) Google Scholar, 7Kopp M.V. Hennemuth I. Dietschek A. Goldstein M. Ihorst G. Heinzmann A. et al.A randomized, double-blind, placebo-controlled trial of probiotics for primary prevention: no clinical or immunological effects of Lactobacillus GG supplementation.Pediatrics. 2008; 121: e850-e856Crossref PubMed Scopus (344) Google Scholar In contrast, among infants from the Kuitunen et al3Kuitunen M. Kukkonen K. Juntunen-Backman K. Korpela R. Poussa T. Tuure T. et al.Probiotics prevent IgE-associated allergy until age 5 years in cesarean-delivered children but not in the total cohort.J Allergy Clin Immunol. 2009; 123: 335-341Abstract Full Text Full Text PDF PubMed Scopus (335) Google Scholar study, similar frequencies of allergic rhinitis (20.7% vs 19.1%) and asthma (13.0% vs 14.1%) were observed 5 years out from intervention. This makes the case for ongoing and future prevention trials to consider evaluating the frequency of allergic respiratory disease at multiple time points over a longer period of time. We do agree with Salfeld and Kopp1Salfeld P. Kopp M.V. Probiotics cannot be generally recommended for primary prevention of atopic dermatitis.J Allergy Clin Immunology. 2009; 124: 170Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar that probiotics should not be considered a universal recommendation for pregnant women with atopic histories. It will be interesting to see if other studies demonstrate a greater therapeutic potential for probiotics for infants born to at-risk women via cesarean deliveries. Probiotics cannot be generally recommended for primary prevention of atopic dermatitisJournal of Allergy and Clinical ImmunologyVol. 124Issue 1PreviewTo the Editor: Full-Text PDF