Synbiotics in patients at risk for spontaneous preterm birth: protocol for a multi-centre, double-blind, randomised placebo-controlled trial (PRIORI)

Abstract

Background: Prematurity remains one of the main causes of neonatal morbidity and mortality. Approximately two thirds of preterm births are spontaneous, i.e. secondary to preterm labour, preterm prelabour rupture of membranes (PPROM) or cervical insufficiency. Etiologically, the vaginal microbiome plays an important role in spontaneous preterm birth (sPTB). Vaginal dysbiosis and bacterial vaginosis are well-known risk factors for ascending lower genital tract infections and sPTB, while a Lactobacillus crispatus-dominated vaginal microbiome is associated with term deliveries. Synbiotics may help to achieve and/or maintain a normal, Lactobacillus-dominated vaginal microbiome.

Methods: We will perform a multi-centre, double-blind, randomised, placebo-controlled trial. Women aged 18 years or older with a singleton pregnancy are eligible for inclusion at 8^0/7-10^6/7 weeks gestational age if they have one or more of the following risk factors for sPTB: previous sPTB at 24^0/7-35^6/7 weeks, prior PPROM before 36^0/7 weeks, or spontaneous pregnancy loss at 14^0/7-23^6/7 weeks of gestation. Exclusion criteria are multiple gestation, cervix conisation, inflammatory bowel disease, uterine anomaly, and the use of pro-/pre-/synbiotics. Patients will be randomised to oral synbiotics or placebo, starting before 11 weeks of gestation until delivery. The oral synbiotic consists of eight Lactobacillus species (including L. crispatus) and prebiotics. The primary outcome is the gestational age at delivery. Vaginal microbiome analysis once per trimester (at approximately 9, 20, and 30 weeks) and delivery will be performed using metataxonomic sequencing (16S rRNA gene) and microbial culture. Secondary outcomes include PPROM, the use of antibiotics, antenatal admission information, and neonatal outcomes.

Discussion: This study will evaluate the effect of oral synbiotics on the vaginal microbiome during pregnancy in a high-risk population and correlate the microbial changes with the gestational age at delivery and relevant pregnancy outcomes.

Trial registration: ClinicalTrials.gov, NCT05966649. Registered on April 5, 2024.

Keywords: Lactobacilli; Next-generation sequencing; PPROM; Pregnancy; Prematurity; Preterm birth; Probiotics; Randomised controlled trial; Synbiotics; Vaginal microbiome.