Home administration of a multistrain probiotic once per day for 4 weeks to newborn infants in Tanzania (ProRIDE): a double-blind, placebo-controlled randomised trial

Background: Probiotics are commonly given to preterm and term infants to reduce gut colonisation and prevent disease. Evidence for the beneficial effect of probiotic therapy is sparse, particularly in term infants from low-income and middle-income countries with high infant morbidity and mortality. This study aimed to assess whether a 4-week course of probiotic therapy might reduce death and hospitalisation up to age 6 months in healthy infants in Tanzania. Methods: In this investigator-initiated, single-site, double-blind, placebo-controlled randomised trial conducted at Haydom Lutheran Hospital and in the surrounding area in northeast Tanzania, we randomly assigned healthy infants born in the hospital, in other local health facilities, or at home who weighed 2 kg or more (1:1) to receive a multistrain probiotic mixture (including Lactobacillus acidophilus, Bifidobacterium bifidum, and Bifidobacterium longum subsps infantis) or placebo once per day for 4 weeks. Caregivers of study participants, investigators, study staff, hospital clinicians, and individuals involved in data management or analysis were masked to treatment allocation during all the data collection and management phases of the trial. Caregivers were shown how to give five drops (0·2 mL) of allocated treatment solution orally to their infant and then requested to administer this treatment once per day for 4 weeks or until the bottle was empty. During scheduled study visits at ages 1 week, 6 weeks, and 6 months, trained field workers visited each participant's home and used a standardised questionnaire to obtain a history of recent illness, medication use, breastfeeding practice, and the current condition of the child. At the 6-week and 6-month follow-up visits, the participants’ weights and lengths were measured, and stool samples were collected. Stool samples were used for analysis of extended-spectrum β-lactamase-producing Enterobacterales (to evaluate gut colonisation rates) and metagenomic sequencing. The primary outcome was a composite of death or hospitalisation during the first 6 months of life, assessed in three populations: a modified intention-to-treat population (mITT), which included all participants with a known primary outcome at 6 months of follow-up; the intention-to-treat population, which included all participants who were enrolled and randomly assigned to a treatment group; and the per-protocol population, which included only infants in the mITT whose caregivers reported having given them the study solution once per day during the 4-week intervention period. This trial is registered with ClinicalTrials.gov, NCT04172012, and is complete. Findings: Between Feb 1, 2022, and Jan 4, 2023, 2000 participants were enrolled and randomly assigned to the probiotic (n=1000) or placebo (n=1000) groups, with administration of the probiotic or placebo treatment beginning on median day 1 (IQR 1–2) of life. 6 months after inclusion, data for the primary outcome were available for 1945 (97·3%) of the 2000 participants. By mITT, there was no statistically significant difference in the primary outcome between the two study groups. Hospitalisation or death occurred in 34 (3%) of 970 participants in the probiotic group and 31 (3%) of 975 participants in the placebo group (crude relative risk 1·10, 95% CI 0·68–1·78). There were also no differences in the overall incidence of adverse events between the groups, but fewer caregiver-reported gastrointestinal events were reported in the probiotic group. Interpretation: Daily administration of a multistrain probiotic mixture in the first 4 weeks of life did not reduce the rate of death or hospitalisation up to age 6 months among infants in Tanzania and did not cause any short-term safety concerns. Funding: Western and Northern Norway Regional Health Authorities, Trond Mohn Foundation, and Joint Programming Initiative on Antimicrobial Resistance.