Early probiotic supplementation for allergy prevention: Long-term outcomes
2012; Elsevier BV; Volume: 130; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2012.07.018
ISSN1097-6825
AutoresMarie P. Jensen, S. J. Meldrum, A. Taylor, Janet A. Dunstan, Susan L. Prescott,
Tópico(s)Probiotics and Fermented Foods
ResumoProgressive change in the patterns and diversity of microbial exposure in early life remains a leading candidate in the rise in many inflammatory diseases. Initial attempts to redress this consequence of modern lifestyle change by using probiotic strains have met with some degree of success in preventing common inflammatory conditions such as allergic diseases. However, much research is still needed to more clearly define optimal early colonization profiles and the best strategies to achieve these. A critical part of this process is understanding long-term and strain-dependent effects, and it is therefore essential that long-term outcomes of early interventions are reported. So far, only 2 randomized placebo-controlled studies have examined long-term (ie, ≥5 years) outcomes.1Kalliomaki M. Salminen S. Arvilommi H. Kero P. Koskinen P. Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.Lancet. 2001; 357: 1076-1079Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar, 2Kalliomaki M. Salminen S. Poussa T. Arvilommi H. Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.Lancet. 2003; 361: 1869-1871Abstract Full Text Full Text PDF PubMed Scopus (1035) Google Scholar, 3Kalliomaki M. Salminen S. Poussa T. Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 1019-1021Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar, 4Kuitunen 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 (327) Google Scholar Both studies used a high-risk cohort and supplemented the children with probiotics pre- (4 weeks) and postnatally (6 months); the study by Kalliomaki et al1Kalliomaki M. Salminen S. Arvilommi H. Kero P. Koskinen P. Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.Lancet. 2001; 357: 1076-1079Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar, 2Kalliomaki M. Salminen S. Poussa T. Arvilommi H. Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.Lancet. 2003; 361: 1869-1871Abstract Full Text Full Text PDF PubMed Scopus (1035) Google Scholar, 3Kalliomaki M. Salminen S. Poussa T. Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 1019-1021Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar used Lactobacillus rhamnosus GG, which significantly reduced the risk of developing eczema during the first 7 years of life; the study by Kuitunen et al4Kuitunen 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 (327) Google Scholar used a probiotic mixture (2 lactobacilli, 1 Bifidobacterium, and 1 Propionibacterium), which significantly reduced the risk of developing IgE-associated allergic diseases, namely, sensitization and eczema, but only for cesarean-delivered children. Here, we report the long-term effects of postnatal supplementation with Lactobacillus acidophilus (LAFTI L10/LAVRI-A1), which was paradoxically associated with an increased risk of sensitization in the first year of life.5Taylor 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 (280) Google Scholar, 6Prescott S.L. Wiltschut J. Taylor A. Westcott L. Jung W. Currie H. et al.Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase.Allergy. 2008; 63: 1481-1490Crossref PubMed Scopus (38) Google Scholar As noted in the original study, the high-risk children in this cohort were randomized to receive L acidophilus or maltodextrin placebo from birth for the first 6 months of life.5Taylor 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 (280) Google Scholar At 5 years of age, all initial participants were invited to a follow-up visit to assess doctor-diagnosed eczema, IgE-mediated food allergy, allergic rhinitis, asthma, and sensitization to common food and aeroallergens, as described more fully in this article's Online Repository at www.jacionline.org. Of the 178 children who completed the supplementation period, 123 attended this 5-year visit, corresponding to a follow-up rate of 69%. Although the loss to follow-up is typical of that reported in other recent long-term randomized control studies,E5Fewtrell M.S. Kennedy K. Singhal A. Martin R.M. Ness A. Hadders-Algra M. et al.How much loss to follow-up is acceptable in long-term randomised trials and prospective studies?.Arch Dis Child. 2008; 93: 458-461Crossref PubMed Scopus (375) Google Scholar the reduction in power (to 70%; see the Online Repository) requires conservative interpretation of the findings. The number and proportion of children who had received the probiotic (n = 66; 54%) and the placebo (n = 57; 46%) were comparable (see Fig E1 in this article's Online Repository at www.jacionline.org), and there were no major differences in the baseline characteristics of the children who were lost to follow-up (n = 55) compared with completers (n = 178) (see Table E1 in this article's Online Repository at www.jacionline.org). At 5 years of age, there were no significant differences (P = .46) in the proportion of children with a current diagnosis of any doctor-diagnosed allergic diseases in the probiotic (n = 28 of 63; 44%) compared with the control group (21 of 56; 38%), although there was a subtle trend for more children in the probiotic group with doctor-diagnosed eczema (P = .08) and recurrent wheezing (P = .06) (Table I). There were no significant differences in sensitization (Table I). This is consistent with previous reports on this cohort5Taylor 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 (280) Google Scholar, 6Prescott S.L. Wiltschut J. Taylor A. Westcott L. Jung W. Currie H. et al.Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase.Allergy. 2008; 63: 1481-1490Crossref PubMed Scopus (38) Google Scholar that this probiotic failed to show any clinical benefits on allergy outcomes at earlier ages, and the longitudinal data are summarized in Table E2 in this article's Online Repository at www.jacionline.org (unadjusted) and Table II (adjusted for the potential confounding influences identified in Table E3 in this article's Online Repository at www.jacionline.org, which did not alter the findings).Table IClinical characteristics of children at 5 years of age: probiotic compared with placebo groupCharacteristic∗All outcomes refer to "recent" symptoms (in the preceding 12 mo) unless otherwise stated.Control(n = 57)Probiotic(n = 66)P valueDiagnosed allergic disease (any)21/56 (38)28/63 (44).46Sensitization (SPT+ to any allergens)20/45 (44)30/57 (53).43Food (any)6/45 (13)13/57 (23).31 Egg (whole fresh egg)3/45 (7)6/57 (11).73 Cow's milk4/45 (9)3/57 (5).70 Peanut4/45 (9)11/57 (19).17Inhalant (any)21/45 (47)30/57 (53).70 House-dust mite13/45 (29)20/57 (35).53 Grass mix11/45 (24)13/57 (23)1.00 Mould mix8/45 (18)11/57 (19)1.00 Cat pelt5/45 (11)12/57 (21).29 Rye grass12/45 (27)16/57 (28)1.00EczemaAny doctor-diagnosed eczema9/56 (16)†Indicates relationships of interest (although not statistically significant).19/62 (31)†Indicates relationships of interest (although not statistically significant)..08†Indicates relationships of interest (although not statistically significant).SPT+ and eczema7/54 (13)13/60 (22).32SCORAD at 5 y, mean ± SEM13.35 ± 2.8013.31 ± 3.45.99SCORAD at worst in last year, mean ± SEM26.41 ± 2.1930.69 ± 3.37.33Respiratory allergyAllergic rhinitis and inhalant SPT+9/50 (18)8/58 (14).60Diagnosed asthma5/57 (9)8/66 (12).77Recurrent cough (without cold)15/57 (26)26/65 (40).13Wheeze the last year6/53 (11)14/64 (22).15Wheeze ever12/57 (21)17/66 (26).67Recurrent wheeze ≥2 episodes0/38 (0)†Indicates relationships of interest (although not statistically significant).5/48 (10)†Indicates relationships of interest (although not statistically significant)..06†Indicates relationships of interest (although not statistically significant).Food allergy (IgE mediated)3/51 (6)8/64 (13).34Unless otherwise stated, values are presented as number of children/sample size (%).SCORAD, Scoring Atopic Dermatitis; SPT, skin prick test.∗ All outcomes refer to "recent" symptoms (in the preceding 12 mo) unless otherwise stated.† Indicates relationships of interest (although not statistically significant). Open table in a new tab Table IIAdjusted∗Adjusted for delivery mode, birth length, head circumference at birth, and maternal age. odds ratios (ORs) and adjusted∗Adjusted for delivery mode, birth length, head circumference at birth, and maternal age. hazard risk (HR) with 95% CIs for the main clinical outcomes in children attending year-1, year-2.5, and year-5 visitsClinical outcomeYear 1 (n = 175)†Clinical history in the preceding year.Year 2.5 (n = 153)‡Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.Year 5 (n = 123)‡Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.Cumulative, years 1-5OR95% CIP valueOR95% CIP valueOR95% CIP valueHR95% CIP valueDiagnosed allergic disease (any)1.260.67-2.37.471.340.68-2.63.400.9560.44-2.08.911.070.80-1.44.63Doctor-diagnosed eczema (any)1.110.59-2.11.741.490.74-2.99.261.950.76-5.03.171.170.83-1.63.37Sensitized (SPT+)2.0§Shaded fields indicate relationships of interest.1.05-4.09§Shaded fields indicate relationships of interest..04§Shaded fields indicate relationships of interest.1.320.62-2.78.471.270.55-2.93.581.270.91-1.78.17SPT+ and eczema2.0§Shaded fields indicate relationships of interest.0.89-4.48§Shaded fields indicate relationships of interest..10§Shaded fields indicate relationships of interest.1.480.63-3.50.371.700.59-4.92.331.5§Shaded fields indicate relationships of interest.0.96-2.42§Shaded fields indicate relationships of interest..07§Shaded fields indicate relationships of interest.Food allergy (IgE mediated)1.650.65-4.22.300.850.33-2.20.731.830.43-7.78.411.170.67-2.02.58Diagnosed asthma———1.550.38-6.23.541.400.39-5.00.61———Allergic rhinitis and inhalant SPT+——————0.5060.16-1.61.25———Boldface indicates statistically significant relationship.SPT, Skin prick test.∗ Adjusted for delivery mode, birth length, head circumference at birth, and maternal age.† Clinical history in the preceding year.‡ Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.§ Shaded fields indicate relationships of interest. Open table in a new tab Unless otherwise stated, values are presented as number of children/sample size (%). SCORAD, Scoring Atopic Dermatitis; SPT, skin prick test. Boldface indicates statistically significant relationship. SPT, Skin prick test. While inevitable dropout rates place some limitation on the interpretation of long-term follow-up studies, these findings nonetheless provide information on long-term effects of early probiotic supplementation for allergy prevention. Consistent with the previous reports from this study, regular dosing with this L acidophilus strain from 0 to 6 months of age had no long-term benefits. The significantly higher rates of sensitization seen at 1 year of age in the probiotic group5Taylor 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 (280) Google Scholar were no longer apparent in the subsequent cumulative analysis (Table II). In the 2 other long-term studies by Kalliomaki et al1Kalliomaki M. Salminen S. Arvilommi H. Kero P. Koskinen P. Isolauri E. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial.Lancet. 2001; 357: 1076-1079Abstract Full Text Full Text PDF PubMed Scopus (2138) Google Scholar, 2Kalliomaki M. Salminen S. Poussa T. Arvilommi H. Isolauri E. Probiotics and prevention of atopic disease: 4-year follow-up of a randomised placebo-controlled trial.Lancet. 2003; 361: 1869-1871Abstract Full Text Full Text PDF PubMed Scopus (1035) Google Scholar, 3Kalliomaki M. Salminen S. Poussa T. Isolauri E. Probiotics during the first 7 years of life: a cumulative risk reduction of eczema in a randomized, placebo-controlled trial.J Allergy Clin Immunol. 2007; 119: 1019-1021Abstract Full Text Full Text PDF PubMed Scopus (363) Google Scholar and Kuitunen et al,4Kuitunen 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 (327) Google Scholar the only beneficial effects found (a decrease in eczema in children supplemented with L rhamnosus GG and a decrease in IgE-associated allergic diseases in cesarean-delivered children supplemented with a probiotic mixture, respectively) remained evident in the follow-up analysis. In both of these studies, the supplements were administered in both the prenatal and the postnatal period, whereas in our study the probiotic was administered only after birth. This has led to speculation that antenatal supplementation is required for optimal effect. However, studies using only postnatal supplementation demonstrated both immunomodulatory effects and eczema prevention7West C.E. Hammarström M.L. Hernell O. Probiotics during weaning reduce the incidence of eczema.Pediatr Allergy Immunol. 2009; 20: 430-437Crossref PubMed Scopus (151) Google Scholar while a study using prenatal L rhamnosus GG found no effect.8Boyle R.J. Ismail I.H. Kivivuori S. Licciardi P.V. Robins-Browne R.M. Mah L.J. et al.Lactobacillus GG treatment during pregnancy for the prevention of eczema: a randomized controlled trial.Allergy. 2011; 66: 509-516Crossref PubMed Scopus (170) Google Scholar Thus, in addition to strain-specific effects,9Wickens K. Black P.N. Stanley T.V. Mitchell E. Fitzharris P. Tannock G.W. et al.A differential effect of 2 probiotics in the prevention of eczema and atopy: a double-blind, randomized, placebo-controlled trial.J Allergy Clin Immunol. 2008; 122: 788-794Abstract Full Text Full Text PDF PubMed Scopus (329) Google Scholar there are likely to be different effects of the timing of administration, which require further research. Strategies to restore favorable patterns and diversity of enteric microflora remain an important avenue for allergy prevention. We acknowledge the staff and volunteers who assisted in this study. We are particularly grateful to the staff in the Children's Allergy Immunology Research (CAIR) team, and the obstetricians and midwives at St John of God Hospital, Subiaco and Murdoch; Mercy Hospital, Mt Lawley; and King Edward Memorial Hospital, Subiaco, Western Australia. The original study has been described in detail previously.E1Taylor 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 (422) Google Scholar Briefly, infants with atopic mothers were randomly assigned within 48 hours of birth to receive placebo (maltodextrin dissolved in 1-2 mL of water) or 3 × 109 colony-forming units of Lactobacillus acidophilus LAFTI L10 (also known as LAVRI-A1) in maltodextrin dissolved in 1 to 2 mL of water on a daily basis to 6 months of age. A total of 178 infants completed the supplementation. Clinical outcomes have been previously assessed at 1 and 2.5 years,E1Taylor 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 (422) Google Scholar, E2Prescott S.L. Wiltschut J. Taylor A. Westcott L. Jung W. Currie H. et al.Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase.Allergy. 2008; 63: 1481-1490Crossref PubMed Scopus (74) Google Scholar and the same methods were used to assess the longer-term allergic outcomes at 5 years of age. Fig E1 shows the number of study participants followed over the course of the study. The study was approved by the ethics committee at the Princess Margaret Hospital as previously indicated.E1Taylor 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 (422) Google Scholar, E2Prescott S.L. Wiltschut J. Taylor A. Westcott L. Jung W. Currie H. et al.Early markers of allergic disease in a primary prevention study using probiotics: 2.5-year follow-up phase.Allergy. 2008; 63: 1481-1490Crossref PubMed Scopus (74) Google Scholar Children were clinically evaluated at 5 years of age by the same pediatrician as at the earlier visits (Prof S. L. Prescott), and the visit included a detailed history, allergy skin prick testing, and physical examinations. A child was classified as having "allergic disease" if he or she had a physician diagnosis of IgE-mediated food allergy, eczema, allergic rhinitis, or asthma at these assessments. The diagnosis of eczema was made in infants with typical skin lesions responsive to topical steroids,E3Hanifen J. Rajka G. Diagnostic features of atopic dermatitis.Acta Derm Venereol. 1980; 92: 44-47Google Scholar and severity was determined by using the Scoring Atopic Dermatitis index.E4Anonymous Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis.Dermatology. 1993; 186: 23-31Crossref PubMed Scopus (1820) Google Scholar Asthma was diagnosed if the child had recurrent wheeze (>2 episodes in the preceding 12 months) and responded to bronchodilator therapy. A diagnosis of allergic rhinitis was made if the child had a clinical history suggestive of allergic rhinitis with evidence of sensitization to inhalants. IgE-mediated food allergy was defined as a history of immediate (within 60 minutes) symptoms after contact with and/or ingestion of food and a positive skin prick test result to the implicated food. Skin prick tests with cow's milk, peanut, house dust mite, cat, grass, mold (Hollister-Stier Laboratories, Spokane, Wash), and whole raw egg were performed. Histamine and glycerine served as positive and negative control, respectively. A wheal diameter of 3 mm or more was considered positive. In addition to the clinical visits, parents recorded data on other symptoms and environmental factors on diary cards. Information on potential confounding factors was collected prospectively (diary cards) and included information on other clinical disease (vaccination, infection, day care, diet, and medication use including antibiotics) and environmental factors (including carpeting, sibship, and pets). Data were analyzed with SPSS software version 19 (SPSS Institute, Inc, Chicago, Ill). Differences between the probiotic group and the placebo group for categorical data were determined by Fisher exact tests or logistic regression. Logistic regression was used to determine the odds ratio of developing each binary allergic outcome in the probiotic group compared with the placebo after adjusting for potential confounding factors (including delivery mode, birth length, birth head circumference, and maternal age). Multivariate Cox proportional hazards regression modeling was used to estimate hazard ratios of developing main allergic outcomes over time and adjusted for the same potential confounding factors included in the logistic regression model. Continuous data were normally distributed and assessed by using Student t test, expressed as means and SEM. A P value of less than .5 was considered statistically significant. A post hoc Wilcoxon-Mann-Whitney power analysis was based on our previous assumptionE1Taylor 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 (422) Google Scholar where an intervention would reduce the risk of developing allergy by 20% with a relative risk of 0.7 and α = .05. The original study, which aimed for 90 subjects in each study group, had more than 80% power to detect this difference in atopic disease. As noted in the main article, 123 of the 178 children who completed the original study supplementation period attended this 5-year visit, corresponding to a follow-up rate of 69%, which is typical of that reported in other recent long-term randomized control studies.E5Fewtrell M.S. Kennedy K. Singhal A. Martin R.M. Ness A. Hadders-Algra M. et al.How much loss to follow-up is acceptable in long-term randomised trials and prospective studies?.Arch Dis Child. 2008; 93: 458-461Crossref PubMed Scopus (375) Google Scholar A post hoc power analysis of this sample size revealed 70% power to detect a 20% fall in the expression of allergy and that a total sample size of 160 had been required to obtain 80% power. This inevitably limits the interpretation of the data from the 5-year visit, and, furthermore, it is difficult to exclude bias in the follow-up population (potentially with higher retention of children with allergic outcomes), and the results have therefore been interpreted conservatively. Although the outcomes of these individuals are not known, the baseline characteristics of the "dropouts" at both the 2.5-year assessment (n = 25, 14%) and the 5-year assessment (n = 55, 31%) are compared with the original study population in Table E1, with no significant differences identified. The number and proportion of 5-year-old children who had received the probiotic and the placebo was n = 66 (54%) and n = 57 (46%), respectively (Fig E1). In the 5-year-old children, we also compared for differences in baseline characteristics between the probiotic and the control groups to identify potential confounding factors (Table E3). There were no major differences in sex, gestation weeks, birth weight, parity, maternal antibiotic usage during breast-feeding, and paternal atopic status. There were also no differences in environmental factors such as dietary patterns, antibiotic usage, and pets, and childcare attendance did not differ significantly between the 2 groups. However, there were considerable differences in maternal age, birth length, and birth head circumference between the 2 groups and a higher proportion of children on probiotics were delivered vaginally (a recognized protective factor from allergic diseaseE6Pistiner M. Gold D.R. Abdulkerim H. Hoffman E. Celedon J.C. Birth by cesarean section, allergic rhinitis, and allergic sensitization among children with a parental history of atopy.J Allergy Clin Immunol. 2008; 122: 274-279Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar). As indicated, we adjusted for any potential confounding effects of these effects in regression analysis, with the adjusted odds ratios and the adjusted hazard ratios for each allergic outcome in relation to the intervention (Table I). Notably, this did not change the findings.Table E1Baseline characteristics of dropouts at 2.5 and 5 years compared with children completing the interventionCharacteristicCompleted intervention (n = 178)Year 2.5 dropouts (n = 25)Year 5 dropouts (n = 55)n (%)n (%)P valuen (%)P valueAt birth Probiotic group89/178 (50)11/25 (44).6722/55 (40).28 Boys87/178 (49)13/25 (52).8330/55 (55).54 Gestation weeks, mean ± SEM39.38 ± 0.8139.34 ± 0.23.8439.37 ± 0.15.95 Vaginal delivery98/178 (55)13/25 (52).8327/55 (49).44 Weight (g), mean ± SEM3466.32 ± 32.543632.12 ± 92.59.083479.85 ± 56.17.84 Length (cm), mean ± SEM50.04 ± 0.1650.14 ± 0.43.8350.05 ± 0.30.99 Head circumference (cm), mean ± SEM34.99 ± 0.1035.40 ± 0.25.1334.97 ± 0.19.94 Parity83/178 (47)12/25 (48)1.0024/55 (44).76 Maternal age (y), mean ± SEM32.82 ± 0.3732.24 ± 0.86.5831.89 ± 0.71.23 Paternal atopy86/176 (49)9/25 (19).2925/54 (46).76During first 6 mo of life Breast-fed ever175/178 (98)25/25 (100)1.0054/55 (98)1.00 Ever had formula123/176 (70)16/25 (64).6439/54 (72).87 Maternal antibiotics while breast-feeding74/176 (42)9/25 (36).6722/54 (41)1.00 Ever had antibiotics39/173 (23)7/25 (28).6112/54 (22)1.00 Pets in household99/176 (49)18/25 (72).1928/54 (52).64 Play group attendance113/176 (64)14/25 (56).5135/54 (65)1.00 Day care attendance16/176 (9)1/23 (4).702/54 (4).26Unless otherwise stated, values are presented as number of children/sample size (%). Open table in a new tab Table E2Unadjusted odds ratios (ORs) and unadjusted hazard ratios (HRs) and 95% CIs for the main clinical outcomes in children attending year-1, year-2.5, and year-5 visitClinical outcomeYear 1 (n = 175)∗Clinical history in the preceding year.Year 2.5 (n = 153)†Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.Year 5 (n = 123)†Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.Cumulative, years 1-5OR95% CIP valueOR95% CIP valueOR95% CIP valueHR95% CIP valueDiagnosed allergic disease (any)1.290.71-2.34.401.410.75-2.68.291.330.64-2.78.441.120.85-1.47.43Doctor-diagnosed eczema (any)1.190.65-2.17.581.560.81-3.02.182.31‡Italicized fields indicate relationships of interest.0.94-5.64‡Italicized fields indicate relationships of interest..07‡Italicized fields indicate relationships of interest.1.230.90-1.69.20Sensitized (SPT+)2.041.07-3.92.031.250.61-2.56.541.390.63-3.05.411.2670.92-1.76.16SPT+ and eczema2.181.01-4.73.0451.520.67-3.45.321.860.68-5.07.231.611.03-2.51.04Food allergy (IgE mediated)1.640.67-4.02.281.000.41-2.471.002.290.57-9.10.241.290.76-2.19.35Diagnosed asthma———1.420.43-4.69.571.430.44-4.66.55———Allergic rhinitis and inhalant SPT+——————0.730.26-2.06.55———Boldface indicates statistically significant relationship.SPT, Skin prick test.∗ Clinical history in the preceding year.† Outcomes at follow-up visits refer to clinical characteristics since the preceding visit.‡ Italicized fields indicate relationships of interest. Open table in a new tab Table E3Baseline characteristics of children completing year-1, year-2.5, or year-5 clinicsCharacteristicYear 1Year 2.5Year 5Control(n = 87)Probiotic(n = 88)P valueControl(n = 76)Probiotic(n = 77)P valueControl(n = 57)Probiotic(n = 66)P valueAt birth Boys44/87 (51)42/88 (48).7639/76 (51)35/77 (45).5227/57 (47)30/66 (45).86 Gestation wk39.44 (0.11)39.31 (0.12).4339.49 (0.12)39.29 (0.13).2439.43 (0.14)39.36 (0.13).72 Vaginal delivery43/87 (49)55/88 (63).1036/76 (47)48/77 (62).1427/54 (48)44/66 (67).04 Weight (g)3521.05 (44.35)3419.11 (48.35).123482.38 (45.12)3395.72 (51.55).213514.79 (54.38)3412.37 (57.67).20 Length (cm)50.46 (0.22)49.66 (0.24).0250.38 (0.25)49.67 (0.25).04550.48 (0.28)49.65 (0.27).03 Head circumference35.20 (0.12)34.81 (0.15).0435.13 (0.13)34.71 (0.16).0435.24 (0.14)34.78 (0.17).04 Parity39/87 (45)42/88 (48).7034/76 (45)37/77 (48).7526/57 (46)33/66 (50).72 Maternal antibiotics while breast-feeding 0-6 mo36/86 (42)37/88 (42)1.0032/74 (43)33/77 (43)1.0022/56 (39)30/66 (45).58 Maternal age (y)32.37 (0.49)33.48 (.50).1232.11 (0.58)33.71 (0.55).04632.86 (0.58)33.56 (0.61).41 Paternal atopy42/87 (48)44/87 (51).8837/75 (49)40/76 (53).7526/57 (46)35/65 (54).47At respective age Ever breast-fed85/87 (98)88/89 (99).6274/76 (97)76/77 (99).6255/57 (96)66/66 (100).21 Ever had formula73/87 (84)72/88 (82).8466/76 (87)61/75 (81).3848/56 (86)54/66 (82).63 Ever had antibiotics41/87 (47)49/88 (56).2959/76 (78)65/76 (86).3052/57 (91)63/66 (95).47 Pets in household40/86 (47)46/88 (52).4532/73 (44)34/74 (46).8724/55 (44)33/66 (50).46 Play group attendance52/86 (60)55/88 (63).8839/75 (51)45/75 (60).4116/52 (31)17/60 (28).84 Day care attendance26/86 (30)26/88 (30)1.0038/75 (51)46/75 (61).2523/53 (43)28/62 (45)1.00Unless otherwise stated values are presented as number of children/sample size (%).Boldface indicates statistically significant relationship. Open table in a new tab Unless otherwise stated, values are presented as number of children/sample size (%). Boldface indicates statistically significant relationship. SPT, Skin prick test. Unless otherwise stated values are presented as number of children/sample size (%). Boldface indicates statistically significant relationship.
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