About this trial
The purpose of this randomized controlled trial is to evaluate the effect of daily supplementation with a probiotic mixture on the neurodevelopmental outcomes of preterm infants with a history of neonatal antibiotic exposure. The intervention lasts for 6 months. The study hypothesizes that early gut microbiota remodeling via exogenous probiotics can improve neurodevelopment. The primary outcome is assessed by the Gesell Developmental Schedules or the Ages \& Stages Questionnaires (ASQ-3). Secondary outcomes include longitudinal changes in gut microbiota composition,targeted metabolomics (such as short-chain fatty acids \[SCFAs\], and systemic inflammatory markers.
Eligibility criteria
This trial does not accept healthy volunteersQualifiers
Preterm infants with a gestational age between 28 and 37 weeks (inclusive of 28 weeks)
Documented history of neonatal intravenous antibiotic exposure for at least 5 consecutive days during the neonatal period (e.g., in the NICU).
Corrected age of 6 months ± 7days at the time of enrollment.
No systemic antibiotic usage within 14 days prior to screening.
Disqualifiers
Severe congenital malformations, chromosomal abnormalities, or inherited metabolic diseases (e.g., Down syndrome).
Severe neurological disorders or structural brain injuries (e.g., Grade III/IV intraventricular hemorrhage, cystic periventricular leukomalacia, or hydrocephalus requiring a shunt).
Severe chronic diseases affecting growth and development (e.g., congenital heart disease requiring surgery, short bowel syndrome, or severe sequelae of necrotizing enterocolitis).
Concurrent participation in other interventional clinical trials.
Trial design
Parallel
Treatments tested in this trial
Probiotic Mixture (Bifidobacterium animalis subsp. lactis Bb-12 and Lacticaseibacillus rhamnosus LGG)
Dietary supplementDaily oral administration of a probiotic mixture containing Bifidobacterium animalis subsp. lactis Bb-12 and Lacticaseibacillus rhamnosus LGG at a dose of 3 x 10\^9 CFU/day for 6 months.
Treatment groups
Trial outcomes
Primary outcomes
Mean Neurodevelopmental Assessment Score
Neurodevelopmental status evaluated using the Gesell Developmental Schedules (yielding Developmental Quotients \[DQs\]) or the Ages \& Stages Questionnaires, Third Edition (ASQ-3). The reported value in the results data table will be the mean score of the participants in each group. * For the Gesell Developmental Schedules: The assessment yields a Developmental Quotient (DQ) for various developmental domains. DQ scores typically range from 0 to over 100, where a score of 100 represents the normative average. Higher DQ scores indicate a better neurodevelopmental outcome (scores below 70 indicate developmental delay). * For the ASQ-3: The questionnaire monitors five developmental domains (Communication, Gross Motor, Fine Motor, Problem Solving, and Personal-Social). Each domain is scored from 0 to 60, yielding a total combined score ranging from a minimum of 0 to a maximum of 300. Higher total scores indicate a better neurodevelopmental outcome.
Secondary outcomes
Change from Baseline in Gut Microbiota Alpha Diversity (Chao1 and Shannon Index Values)
Evaluation of longitudinal changes in gut microbiota alpha diversity based on 16S ribosomal RNA (16S rRNA) gene sequencing. The results data table will report the mean change from baseline in Chao1 and Shannon indices (dimensionless scores).
Relative Abundance of Specific Gut Microbiota Taxa
The percentage of key bacterial groups (specifically targeting the supplemented strains Bifidobacterium and Lacticaseibacillus) relative to total sequences, determined via 16S rRNA gene sequencing. The results data table will report the mean relative abundance percentage (%)
Concentration of Fecal Short-Chain Fatty Acids (SCFAs)
Concentrations of specific fecal short-chain fatty acids (including acetate, propionate, and butyrate) quantified using gas chromatography-mass spectrometry (GC-MS) targeted metabolomics. The results data table will report the mean concentration in micromoles per gram (umol/g) of wet feces.
Concentration of Systemic Inflammatory Markers
Circulating levels of specific systemic inflammatory mediators (specifically Interleukin-6 \[IL-6\] and Tumor Necrosis Factor-alpha \[TNF-ɑ\]) measured in blood samples using Enzyme-Linked Immunosorbent Assay (ELISA) to evaluate host-microbe signaling pathways. The results data table will report the mean concentration in picograms per milliliter (pg/mL)
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