Application of Lactobacillus Salivarius CECT5713 in Infertility of Unknown Origin

Application of Lactobacillus Salivarius CECT5713 to Achieve Term Pregnancies in Women With Repetitive Abortion or Infertility of Unknown Origin by Microbiological and Immunological Modulation of the Vaginal Ecosystem

In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble immune factors and bacterial profile) in women with reproductive failure because of either repetitive abortion or infertility of unknown origin and compare it to that of healthy fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius CECT5713 to modulate such parameters and to increase pregnancy rates in women with reproductive failure. The administration of L. salivarius CECT5713 (~9 log10 colony-forming units (CFU)/day) for 6 months or until a diagnosis of pregnancy to women with reproductive failure resulted in an overall successful (term) pregnancy rate of 56%.

Study Overview

• Status: Completed
• Conditions: Abortion in First Trimester; Abortion, Spontaneous; Infertility Unexplained
• Intervention / Treatment: Biological: Lactobacillus salivarius CECT5713

Detailed Description

In this study, we aimed to assess the cervicovaginal environment (pH, Nugent score, soluble immune factors and bacterial profile) in women with reproductive failure because of either repetitive abortion or infertility of unknown origin and compare it to that of healthy fertile women. The second objective was to evaluate the ability of Lactobacillus salivarius CECT5713 to modulate such parameters and to increase pregnancy rates in women with reproductive failure. Vaginal pH and Nugent score were higher in women with reproductive failure than in fertile women. Differences were also noted regarding soluble immune factors transforming growth factor beta (TGF-β) and vascular endothelial growth factor (VEGF). Their concentrations in cervicovaginal lavage samples were reduced by about one-half in women with reproductive failure compared to fertile women. Lactobacilli were detected in a higher proportion, and at a higher concentration and having different species profile, in fertile women than in women with repetitive abortion or infertility. The study of the vaginal microbiome revealed that samples from fertile women were characterized by the high abundance of Lactobacillus sequences, while in about one third of samples from women with reproductive failure DNA from this genus was practically absent while there was an abundance of that of Gardnerella and Bifidobacterium. Lactobacillus salivarius CECT5713 seemed to be a suitable candidate to modulate the cervicovaginal microbiota because of its acidifying capacity, adhesion to vaginal cells and co-aggregation with vaginal pathogens. The administration of L. salivarius CECT5713 (~9 log10 CFU/day) for 6 months or until a diagnosis of pregnancy to women with reproductive failure resulted in an overall successful (term) pregnancy rate of 56%. In addition, the probiotic intervention modified significantly key microbiological, biochemical and immunological parameters in women who got pregnant being their post-intervention values similar or close to those of fertile women. The high concentrations of L. salivarius and the detection of L. salivarius DNA in vaginal samples confirmed that the probiotic was able to reach the vaginal mucosa. In conclusion, L. salivarius CECT5713 has proved to be a good candidate to improve reproductive success in women with reproductive failure.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2

Contacts and Locations

Study Locations

• Spain
  • Madrid, Spain, 28040
    • Dpt. Nutricion, Bromatologia y Tecnologia de los Alimentos

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 33 years to 41 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Recurrent miscarriage with three or more pregnancy losses during the first 12 weeks of pregnancy (RA group)
• Infertility (inability to conceive) despite being the recipients of ART for at least three times, including two cycles, at least, of in vitro fertilization (IVF) (INF group).
• Fertile women having at least two children after uncomplicated term pregnancies (Control group).

Exclusion Criteria:

• Antiphospholipid syndrome
• Hormonal therapy, antibiotics or probiotics in the 4 weeks previous to sampling.
• Lactose intolerance or cow's milk protein allergy (RA and INF groups)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Repetitive Abortion (RA) group; Starting at day 0, women of the RA (n=21) group consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).	Biological: Lactobacillus salivarius CECT5713; Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
Experimental: Infertility (INF) group; Starting at day 0, women of the INF group (n=23) consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).	Biological: Lactobacillus salivarius CECT5713; Starting at day 0, women of the RA and INF groups consumed (oral route) a daily sachet with ~50 mg of freeze-dried probiotic (~9 log10 CFU of L. salivarius CECT5713) for 6 months or until a diagnosis of pregnancy (whatever happened first).
No Intervention: Control group; The control group (n = 14) included fertile women having at least two children after uncomplicated term pregnancies.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pregnancies and successful pregnancies	Total number of pregnancies and number of pregnancies with delivery of a healthy baby	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Modification of the vaginal microbiota	Variation in the concentration of lactobacilli and other bacteria in cervicovaginal lavage samples	6 months
Vaginal immunomodulation	Variation in the concentration of TGF-β and VEGF in cervicovaginal lavage	6 months

Collaborators and Investigators

• Sponsor: Universidad Complutense de Madrid
• Collaborators: Bisearch Life; Centro de Diagnóstico Médico. Ayuntamiento de Madrid.
• Investigators: Principal Investigator: Juan M Rodriguez, PhD, Complutense University Madrid

Study record dates

Study Major Dates

• Study Start (Actual): October 16, 2018
• Primary Completion (Actual): November 29, 2019
• Study Completion (Actual): November 29, 2019

Study Registration Dates

• First Submitted: June 22, 2020
• First Submitted That Met QC Criteria: June 22, 2020
• First Posted (Actual): June 25, 2020

Study Record Updates

• Last Update Posted (Actual): June 26, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Infertility; Abortion
• Additional Relevant MeSH Terms: Pregnancy Complications; Infertility; Abortion, Spontaneous
• Other Study ID Numbers: PREPROBIFERT01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Global and individual microbiological and immunological data will be available to other researchers once the study is published.
• IPD Sharing Time Frame: The data will be available to other researchers once the study is published.
• IPD Sharing Access Criteria: On request
• IPD Sharing Supporting Information Type: Study Protocol; Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No