Treatment of the Intermediate Vaginal Microbiota With Vaginal Lactobacillus Casei Rhamnosus to Improve Pregnancy Outcome
Condition: Lactobacillus Infection
Study type: Interventional
Phase: Phase 3

Summary: 
      In the currently presented trial, investigators aim to evaluate the treatment of the
      intermediate vaginal microbiota during the first trimester of pregnancy with vaginal
      lactobacilli to restore the normal vaginal microbiota and therewith reduce the rate of PTD.
      All pregnant women between 10 + 0 (10 weeks plus 0 days) and 16 + 0 (16 weeks plus 0 days)
      gestational weeks in study group will be treated with vaginal Lactobacilli Capsules
      containing L. Casei rhamnosus LCR 35
    

Detailed description: 
      Despite recent achievements in perinatal care, the prevention of preterm delivery (PTD)
      remains a major challenge in modern obstetrics. Healthy vaginal flora, dominated by
      Lactobacillus species (spp.), plays an important role in the protection against genital
      infections, which are considered a frequent cause of PTD. Imbalances of the vaginal flora
      caused by a reduction in the proportion of Lactobacillus spp. can lead to an overgrowth of
      mixed anaerobic bacteria, which can ultimately result in bacterial vaginosis (BV). Since the
      effect of treating pregnant women with an abnormal vaginal flora was introduced, BV has
      gained interest and is now a well-known risk factor for ascending infections and subsequent
      PTD. However, the overall risk reduction of PTD through antibiotic treatment of an abnormal
      flora was disproved by large and well-designed studies in a general obstetrical population.

      At present, little is known about the role of the intermediate vaginal flora, which can
      either be regarded as the transition from a healthy to an abnormal flora or as the transition
      from abnormal flora back to a healthy vaginal microbiota. The intermediate vaginal flora
      constitutes a highly heterogeneous group that may or may not include vaginal Lactobacillus
      spp. and that may or may not be characterised by the presence of anaerobic bacteria. In 2007,
      a meta-analysis reported that the presence of intermediate vaginal flora was not associated
      with PTD, late miscarriage, maternal or neonatal infection, or perinatal mortality. In
      contrast, an observational study by Hay et al.reported a high rate of late miscarriage (16-24
      gestational weeks) in women with intermediate vaginal flora at an examination before 16
      gestational weeks. Additionally, another study reported an association of PTD with partial
      BV, which is defined as streaks of BV flora in a smear that has areas of normal flora.

      Latest research reported that there is an association between the intermediate vaginal flora
      and PTD. In one of our previous studies, intermediate flora was identified on the examined
      screening smears of 529/8421 (6.3%) women. In this group, 349/529 (66%) women had a Nugent
      score of 4, 94/529 (17.8%) had a Nugent score of 5, and 86/529 (16.2%) had a Nugent score of
      6. In women with a Nugent score of 4, 232/349 (66.5%) women were assigned to the Lactobacilli
      group. The Non-Lactobacilli group consisted of 117/349 (33.5%) women with a Nugent score of 4
      due to the total absence of any bacterial colonisation, including Lactobacillus spp. The
      preterm delivery rate was significantly lower in the Lactobacilli than in the
      Non-Lactobacilli group On follow-up smears, bacterial vaginosis rates were 9% in the
      Lactobacilli and 7.8% in the Non-Lactobacilli group. Hence, according to this retrospective
      study, the absence of vaginal Lactobacillus species and any bacterial colonisation increases
      the risks of preterm delivery and low birth weight in women with intermediate vaginal flora
      in early pregnancy.

      In the currently presented trial, investigators aim to evaluate the treatment of the
      intermediate vaginal flora during the first trimester of pregnancy with vaginal lactobacilli
      to restore the normal vaginal microbiota and therewith reduce the rate of PTD.

      At investigators Department, pregnancy care includes a prenatal consultation, where women
      registered for a planned delivery at our department between 10 + 0 (10 weeks plus 0 days) and
      16 + 0 (16 weeks plus 0 days) gestational weeks. Women underwent routine screening for
      asymptomatic vaginal infections and characterization due to Nugent score. All women except
      those with a normal flora (Nugent score 0 to 3) will be asked to undergo a follow-up smear
      between 14 + 0 (14 weeks plus 0 days) and 22 + 0 (22 weeks plus 0 days) gestational weeks at
      our department. Vaginal smears will be obtained after vaginal fluid collection with sterile
      swabs from the lateral vaginal wall and posterior fornix vaginae. Both at first and control
      smear. All smears will be Gram-stained and microscopically analyzed by one of four biomedical
      laboratory assistants, specialized in gynecological cytopathology, at a laboratory that is
      certified according to DIN EN ISO 9001:2008. Nugent scores of 0 to 3 will be considered to
      indicate normal vaginal flora, 4 to 6 to indicate intermediate vaginal flora, and 7 to 10 to
      indicate BV.

      The present study follows a prospective randomized observer-blinded mono-centric design.
      After obtaining the results of vaginal swab According to the Nugent scoring system, two
      groups will be assigned: (i) pregnant women with an intermediate vaginal flora and a Nugent
      score of 4 with vaginal lactobacilli (Control Group), versus (ii) pregnant women with an
      intermediate vaginal flora and a Nugent score of 4 without vaginal lactobacilli (Study
      Group).

      Therapy will be assigned due to protocol. Each group will be divided in a study and control
      group. Patients of the study group will be treated with muco-adhesive slow release vaginal
      tablets containing 876,9 mg Lactobacillus casei rhamnosus (Lcr regenerans) in concentration
      of 107 CFU/ml (Groups A + C). The treatment duration will be 8 days with two tablets every
      4th day. Patients of the control group will not undergo any treatment (Groups B + D). A
      vaginal control smear will be obtained 4-6 weeks following the first study visit.

      The primary outcome parameter will be the recovery to the normal vaginal flora (Nugent score
      0 to 3). Secondary outcome parameters will include (i) the gestational age at delivery,
      recorded as term delivery at or after 37 + 0 gestational weeks, (ii) the rate of PTD, defined
      as spontaneous delivery at or before 36 + 6 gestational weeks, due to preterm premature
      rupture of the membranes and/or preterm labor, (iii) neonatal birthweight, defined as a the
      weight at the time of delivery, and (iv) the rate of live birth, defined as the delivery or
      PTD of an infant that had an Apgar score at 1 minute of > 0.
    

Intervention name(s): Lactobacillus casei rhamnosus (Lcr 35 regenerans); NO Intervention
Intervention type(s): Drug; Other
Intervention description(s): Probiotic vaginal tablets vith active probiotic strains; NO Intervention
Other intervention name(s): Gynophilus; NO Medication
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Prevention