Preterm-birth-prevention with Lactobacillus Crispatus oral probiotics: Protocol for a double blinded randomised placebo-controlled trial (the PrePOP study).

Introduction: Effective spontaneous preterm birth (sPTB) prevention is an urgent unmet clinical need. Vaginal depletion of Lactobacillus crispatus is linked to sPTB. This trial will investigate impact of an oral Lactobacillus spp. probiotic product containing an L. crispatus strain with other Lactobacilli spp., on the maternal vaginal and gut microbiome in pregnancies high-risk for sPTB.

Methods: A double-blind, placebo-controlled, randomised trial will be performed at the National Maternity Hospital Dublin, Ireland. Inclusion criteria are women with history of sPTB or mid-trimester loss, cervical surgery (cone biopsy or two previous large-loop-excision-of-transformation-zone) or uterine anomaly. The intervention is oral supplementation for twelve weeks with probiotic or identical placebo. The probiotic will contains: ◦ 4 billion CFU Lactobacillus crispatus Lbv 88(2x10⁹CFU/Capsule) ◦ 4 billion CFU Lactobacillus rhamnosus Lbv 96(2x10⁹CFU/Capsule) ◦ 0.8 billion CFU Lactobacillus jensenii Lbv 116(0.4x10⁹CFU/Capsule) ◦ 1.2 billion CFU Lactobacillus gasseri Lbv 150(0.6x10⁹CFU/Capsule) Investigators and participants will be blinded to assignment.

Results: The primary outcome is detectable L. crispatus in the vaginal microbiome after twelve weeks of treatment, measured using high-throughput DNA sequencing. A total of 126 women are required to detect a 25 % increase in detectable L. crispatus. Secondary outcomes include impact of intervention on the gut microbiome and metabolome, rate of sPTB and mid-trimester loss, neonatal outcomes and maternal morbidity.

Conclusions: This randomised trial will investigate ability of an oral probiotic containing L. crispatus to increase its abundance in the vaginal microbiome, both directly by horizontal transfer and indirectly via microbiome and metabolome of the gut.