We previously reported the initial results of the Trial of Infant Probiotic Supplementation (TIPS) study to determine if daily administration of a probiotic, Lactobacillus rhamnosus GG (LGG), during the first 6 months of life to children at high risk for allergic disease because of asthma in a parent can decrease their cumulative incidence of eczema.1 To date, the TIPS study is the only of its type performed in the United States.urour initial report, when all children were at least 2 years of age, we noted no effect on the incidence of eczema. We now present additional results, with the participants at least 7 years of age, on the cumulative incidence of eczema, asthma, and rhinitis.
Methods
The TIPS study is a randomized, double-masked, parallel-arm, controlled trial designed to evaluate the effectiveness of daily LGG supplementation for the first 6 months of life to decrease the incidence of eczema, a potential early marker of asthma.1 For this analysis, we used physician-diagnosed asthma and physician-diagnosed rhinitis as secondary outcomes.
To determine the effects of LGG on cumulative incidence of study outcomes, we performed modified intention-to-treat analyses with all participants who received treatment in the study arm to which they had been randomly assigned. We used survival analysis approaches to estimate Kaplan-Meier curves for each treatment group. We used nonparametric log-rank tests to determine differences between treatment groups and failure plots to visualize the cumulative probability of experiencing each outcome during follow-up.
We used separate Cox proportional hazards regression models to compare the incidence of each outcome between the intervention and control groups, adjusting for mode of delivery and breastfeeding duration. Breastfeeding duration (in months up to 12) was treated as a time-dependent covariate.
All analyses were performed using SAS version 9.4 software (SAS Institute Inc, Cary, NC). P < .05 was set for statistical significance. The protocol was approved by the Albert Einstein College of Medicine Institutional Review Board.
Results
Over the 7-year follow-up, 49 (53%) of 92 intervention and 54 (59%) of 92 control participants remained in the study for an overall 56% retention rate. Eczema was diagnosed in 78 participants, asthma in 32, and rhinitis in 15. The mean follow-up time was 5.7 years (median, 7 years). Incidence of eczema was high during infancy but low thereafter. In contrast, incidence rates for asthma and rhinitis were constant during childhood. Although the initial cumulative incidence seemed to favor the intervention in the early years of life for eczema and asthma, this trajectory was not sustained. The results showed no difference in the primary or secondary outcomes (Fig 1). Main findings from the Cox proportional hazards regression model are presented in Table 1. Cesarean delivery was associated with a greater incidence of rhinitis, with a hazard ratio (HR) of 3.33 (95% confidence interval [CI], 1.21–9.21).
Kaplan-Meier failure curves for follow-up over 7 years. A, Eczema. B, Asthma. C, Rhinitis.
Kaplan-Meier failure curves for follow-up over 7 years. A, Eczema. B, Asthma. C, Rhinitis.
Cox Proportional Hazards Regression Models Evaluating the Incidence of Eczema, Asthma, and Rhinitis
| Eczema | Asthma | Rhinitis | |
|---|---|---|---|
| Intervention group | 1.00 (0.64–1.57) | 0.91 (0.45–1.82) | 1.39 (0.49–3.91) |
| Cesarean deliverya | 1.30 (0.79–2.16) | 1.44 (0.69–3.00) | 3.33 (1.21–9.21) |
| Breastfedb | 11.97 (6.81–21.02) | 1.00 (1.00–1.00) | 0.00 (0.00–infinity) |
| Eczema | Asthma | Rhinitis | |
|---|---|---|---|
| Intervention group | 1.00 (0.64–1.57) | 0.91 (0.45–1.82) | 1.39 (0.49–3.91) |
| Cesarean deliverya | 1.30 (0.79–2.16) | 1.44 (0.69–3.00) | 3.33 (1.21–9.21) |
| Breastfedb | 11.97 (6.81–21.02) | 1.00 (1.00–1.00) | 0.00 (0.00–infinity) |
Data are presented as adjusted HR (95% CI).
n = 47 participants (26 in intervention group, 21 in control group).
n = 88 participants breastfed for at least 12 mo (47 in intervention group, 41 in control group).
Discussion
This follow-up report reveals that early infant LGG supplementation does not affect the cumulative incidence of eczema, asthma, and rhinitis at 7 years of age. Kalliomäki et al2 reported that early LGG supplementation decreases the likelihood of eczema and wheezing; however, their LGG supplementation occurred through both postnatal infant and prenatal maternal supplementation. The effect of LGG supplementation may only be discernable in infants born into high-risk scenarios because of altered gastrointestinal microbiota development3,4 (eg, cesarean delivery, lack of breast milk exposure); however, few TIPS study infants were exclusively fed formula or were cesarean delivered. Although LGG supplementation in infants is associated with significant increases in the similarity of the infant gut microbiota and metabolome to that of an infant at low risk for allergic disease, it does so only for the 6-month period in which LGG is administered.5 It is possible that probiotic supplementation to the mother during pregnancy and/or the infant for a longer period may be more effective.
The results presented in Table 1 reveal that breastfeeding may increase the risk of eczema (HR, 11.97); however, the CIs are extremely wide (95% CI, 6.81–21.02), suggesting an unstable estimate. In addition, the effect of breastfeeding is not consistent, as there is no association with asthma or rhinitis incidence; therefore, we cannot clearly interpret this result. There is the potential of a type II error, as the TIPS study was designed to have 80% power to detect an HR <0.66, corresponding with a 10% absolute reduction in the 2-year cumulative incidence of eczema.
Despite these limitations of the results, we can build on our earlier report regarding eczema. For this population of infants at higher risk for allergic disease, we cannot support the use of early infant LGG probiotic supplementation for the prevention of eczema, asthma, or rhinitis.
Dr Cabana conceptualized and designed the study, designed the data collection instruments, and drafted the initial manuscript; Dr LeCroy performed the analyses and reviewed and revised the manuscript; Ms Menard-Livingston collected data and reviewed and revised the manuscript; Dr Rodgers coordinated and supervised data collection and critically reviewed the manuscript; Ms McKean designed the study, supervised and coordinated the overall data collection, and critically reviewed the manuscript; Drs Caughey, Wong, and Leong supervised the data collection and critically reviewed the manuscript; Drs Fong and Lynch contributed to the study design and critically reviewed the manuscript; Dr Boushey contributed to the study design, designed the data collection instruments, and critically reviewed the manuscript; Dr Hilton designed the study analysis plan and critically reviewed the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
This trial has been registered at www.clinicaltrials.gov (identifier NCT00113659).
FUNDING: This study was funded by the National Institutes of Health (grant HL 080074) and the Clinical and Translational Science Institute (grant UL1 RR024131). Amerifit Brands provided control capsules for the intervention. Neither the National Institutes of Health nor Amerifit Brands had a role in the design and conduct of the study. Funded by the National Institutes of Health (NIH).
CONFLICT OF INTEREST DISCLOSURES: The authors have indicated they have no conflicts of interest relevant to this article to disclose.
Comments
Unfortunately, the author of the comment above fails to recognize the study design
The control group did receive a slightly higher dose of inulin compared to the intervention group (100 mg/day). However, the typical minimal dose for any prebiotic effect of inulin is 2000 mg/day--an order of magnitude in difference. In addition, for children, most studies have used doses of 6000 to 8000 mg/day (Swanson, 2020). It unlikely that this difference in the dose of inulin, a fraction of its therapeutic dose, had any clinical effect.
Cabana MD, McKean M, Caughey AB, Fong L, Lynch S, Wong A, Leong R, Boushey HA, Hilton JF. Early Probiotic Supplementation for Eczema and Asthma Prevention: A Randomized Controlled Trial. Pediatrics. 2017 Sep;140(3):e20163000. doi: 10.1542/peds.2016-3000.
Swanson KS, de Vos WM, Martens EC, Gilbert JA, Menon RS, Soto-Vaca A, Hautvast J, Meyer PD, Borewicz K, Vaughan EE, Slavin JL. Effect of fructans, prebiotics and fibres on the human gut microbiome assessed by 16S rRNA-based approaches: a review. Benef Microbes. 2020 Mar 27;11(2):101-129
Fundamental Design Flaw