Effectiveness of a Molecular Biology Screen-and-Treat Strategy Using Metronidazole and Combination Therapy for Vaginal Flora Abnormalities in High-Risk Pregnancies

The primary objective is to evaluate the efficacy of a screen-and-treat strategy for vaginal flora abnormalities using point-of-care (POC) multiplex technology before 18 weeks’ gestation to reduce the rate of preterm birth in pregnant women at high risk. This population includes individuals with a history of preterm birth or late fetal loss. The intervention is compared against a conventional strategy involving no screening. 5

The secondary objectives include the assessment of the following outcomes:

• The rate of preterm birth after 22 weeks' gestation and the severity of prematurity based on gestational age at birth.
• Pregnancy morbidity and the rate of spontaneous abortion between 14 and 22 weeks' gestation.
• Neonatal mortality and morbidity at the end of hospitalization, alongside the total inpatient stay for both the mother and the newborn.
• In the intervention group, the effectiveness of personalized treatment on the microbiota and targeted microorganisms via polymerase chain reaction (PCR), the frequency of POC positivity recurrence, and the risk of preterm birth following successful treatment.
• The comparison of preterm birth risk associated with vaginal dysbiosis, infection, or specific species identified by POC.
• In the control group, the frequency and type of bacterial vaginosis diagnosis using conventional methods, including screening for recurrence and treatments.
• Cost-effectiveness and budgetary impact analysis of the screen-and-treat strategy.
• Exploratory metagenomic and culturomic analysis.

The sponsor did not provide information regarding the total number of participants. The study population consists of pregnant women who are considered vulnerable. Eligible participants include females aged 18 years or older with a single intrauterine pregnancy between 8 and 18 weeks of gestation. The cohort is characterized by a history of preterm birth before 37 weeks or late fetal loss. Inclusion is based on the presence or absence of symptoms related to bacterial vaginosis or vaginal flora abnormalities. Participants must be affiliated with a social security regimen or equivalent.

This multicentre, randomized study is designed to evaluate a screen-and-treat strategy for vaginal flora abnormalities in pregnant women at high risk of preterm birth. The trial utilizes a molecular biology approach with POC multiplex technology to detect conditions such as bacterial vaginosis before 18 weeks of gestation. Participants are assigned to either an experimental group receiving the innovative screening and treatment strategy or a standard care group without screening. The primary endpoint is the rate of delivery before 37 weeks of gestation. The study involves a screening visit to identify eligible participants between 8 and 18 weeks of gestation, followed by treatment or standard management and subsequent follow-up to monitor clinical outcomes, including morbidity, neonatal mortality, and recurrence of abnormalities. The overall trial duration is estimated to span from April 2026 to April 2030. Study involvement concludes with the end-of-study assessment following delivery and neonatal discharge.

The study involves the administration of several experimental treatments. Clotrimazole is provided as a 500 mg soft capsule for vaginal use.

Metronidazole is administered as a 1 g film-coated tablet via the oral route.

Azithromycin dihydrate is administered as a 1 g film-coated tablet via the oral route.

Ceftriaxone and lidocaine hydrochloride monohydrate are administered as a 1 g solution for injection via intramuscular injection.

Doxycycline (anhydrous) is administered as a 200 mg film-coated tablet via the oral route.

The primary efficacy endpoint is the rate of preterm birth occurring before 37 weeks of gestation, which will be compared between the experimental group and the standard care group. Secondary endpoints include various severity criteria of prematurity, specifically the rates of delivery at several gestational intervals before 37 weeks. Morbidity during pregnancy will be assessed through the rate of preterm rupture of the membranes, determined by clinical observation or a positive AmniSure, Actim PROM, or Amnicator test. Other pregnancy morbidity measures include the rate of late fetal loss between 14 and 22 weeks of gestation, fetal growth restriction measured by abdominal or femoral circumference, endometritis identified by clinical symptoms and vaginal swabbing, and the rate of spontaneous preterm birth. Additional parameters include the rate of risk of preterm birth assessed via vaginal ultrasound for cervical length, the rate of progestative treatment, and the rate of emergency cerclage. Neonatal mortality and neonatal morbidity, such as respiratory distress syndrome or necrotizing enterocolitis, will be evaluated until hospital discharge.

In the experimental group, the effectiveness of the treatment is evaluated by comparing quantitative loads of hosts measured via molecular biology before and after treatment. This group's assessment includes the rate of successful treatment, determined by a negative molecular analysis at the first vaginal sample control, and the rate of recurrence, defined by a positive result following a negative control during follow-up. Further analyses for this group include the rate of positivity for each host and the rate of preterm birth stratified by initial treatment success and POC test results. In the standard care group, the proportion and management of bacterial vaginosis will be evaluated using traditional methods such as the Nugent score. The study also includes health economic assessments, including the incremental cost-effectiveness ratio and budget impact, alongside metagenomic and culturomic exploratory analyses.