Abstract

Background: Prior spontaneous preterm birth (sPTB) confers substantial recurrence risk. We tested whether a targeted, lactate-yielding, glycogen-mimetic vaginal prebiotic could modulate cervicovaginal biology linked to sPTB. Methods: In a double-blind, randomized, placebo-controlled trial (n=50; 25 per arm), participants enrolled at 14–20+6 weeks’ gestation used nightly pessaries followed by alternate-night dosing to 28 weeks. The prespecified primary endpoint was change from baseline to 8 weeks in a composite inflammatory-risk score integrating log-transformed, standardized IL-1β, IL-8, and TNF-α with qualitative fetal fibronectin (fFN). Secondary outcomes included individual cytokines, vaginal pH, Lactobacillus dominance and Shannon α-diversity, fFN positivity, and exploratory clinical outcomes. Analyses used two-sided tests with α=0.05. Results: The prebiotic achieved a significantly greater reduction in the composite inflammatory-risk score versus placebo (−0.78±0.95 vs −0.06±0.66; p=0.003). Individual cytokine changes favored the prebiotic without reaching significance. At 8 weeks, vaginal pH was lower with prebiotic than placebo (4.22±0.30 vs 4.44±0.34; p=0.017), and among participants with baseline pH>4.5, normalization to ≤4.5 occurred more often with prebiotic (68% vs 38%; p=0.046). Microbiome profiling demonstrated a greater rise in Lactobacillus dominance and a larger decrease in Shannon α-diversity with prebiotic (both p=0.045). fFN positivity was numerically lower with prebiotic (12% vs 28%) but not significant. Exploratory clinical outcomes, including gestational age at delivery, PROM/PPROM, and NICU admission, showed nonsignificant, favorable directions for the prebiotic. Conclusions: In high-risk pregnant individuals with prior sPTB, a targeted vaginal prebiotic favorably modulated a composite inflammatory-risk score, reduced vaginal pH, and shifted the microbiome toward a Lactobacillus-dominant, lower-diversity state, consistent with the proposed mechanism of action. Although clinical outcomes were underpowered and not significantly different, coherent biomarker and ecological improvements support the biological plausibility and feasibility of cervicovaginal prebiotic therapy for sPTB risk modification. Larger trials are warranted to confirm clinical efficacy and refine composite endpoints for decision-making in future studies.