Oral Probiotic Supplementation in Pregnancy to Reduce Group B Streptococcus Colonization (OPSiP)

This is a double-blind randomized placebo controlled trial that will investigate whether the use of three specific species of probiotics taken orally in pregnancy from 25 weeks gestation will reduce the incidence of Group B Streptococcus (GBS) colonization. Participants will take 2 capsules and 1 lozenge per day of either probiotic or placebo from 25 weeks gestation. The primary outcome will be the study-specific vaginal/rectal swab collected after 35 weeks gestation and before delivery. A reduction in women testing positive for GBS would lead to a decrease risk to infants of GBS infection and a reduction in the use of antibiotics leading to less maternal and neonatal antibiotic exposure.

Study Overview

• Status: Active, not recruiting
• Conditions: Group B Streptococcus Carrier in Childbirth
• Intervention / Treatment: Dietary supplement: Probiotic supplementation; Other: Placebo

Detailed Description

Background:

Group B streptococcus (GBS) infection of the newborn is a leading cause of neonatal morbidity and mortality in North America. Up to 30% of pregnant women are colonized with GBS. Half of the babies born to colonized mothers will become colonized themselves, and of those, about 1-2% may develop early onset GBS infection (EOGBS), which is associated with significant mortality (between 5% and 20%) and morbidity (71% bacteremia, 11% meningitis, 19% pneumonia). The current recommendation is for routine administration of IPA to women who test positive for GBS at term. Although IPA therapy may reduce the incidence of neonatal GBS infection, it can increase the risk of other infections such as E. Coli, neonatal thrush, and ampicillin resistant Enterobacteriaceae.

There is also accumulating evidence linking antibiotics in pregnancy with childhood asthma, childhood obesity, and obesity in later life. IPA is also associated with antibiotic resistance, diarrhoea (including Clostridium difficile), and fungal infections. There is a growing worldwide interest in utilizing probiotics to enhance and manipulate the human microbiome in order to reduce a wide range of communicable and non-communicable diseases. Probiotics have been studied extensively in pregnant women and are considered safe and well tolerated when ingested or used vaginally.

Probiotics in pregnancy may reduce GBS colonization and the need for intrapartum antibiotic prophylaxis through a number of mechanisms. Some probiotics produce antibacterial substances and film-like barriers to pathogens. By adhering to vaginal epithelial cells, probiotics also displace pathogens such as GBS. S. salivarius K12 has been shown to inhibit several GBS strains, including disease-implicated isolates from newborns and colonizing isolates from the vaginal tract of pregnant women. In vivo and in vitro studies demonstrate its ability to adhere to the vaginal epithelium and directly impair the growth and adherence of GBS.

Several pilot randomized trials of L. reuteri and L. rhamnosus show promise in their their ability to reduce GBS colonization and have been shown to be safe. In vivo and in vitro studies of various lactobacillus strains, including rhamnosus and reuteri, have demonstrated an inhibitory effect on GBS.

Preliminary research to date suggests the administration of probiotic supplements to women in pregnancy may reduce the incidence of GBS colonization, thus reducing the need to administer intravenous prophylactic antibiotics (IPA) to women during labour. The specific species of probiotics chosen for this trial create a combination of inhibitory and antibacterial effects that may result in a greater reduction of GBS colonization than shown in previous trials.

The study:

The OPSiP study is a three-year, two-centre, double blind randomized placebo controlled trial. The aim of this study is to assess if a combined daily oral supplementation of Lactobacillus rhamnosus, Lactobacillus reuteri and Streptococcus salivarius beginning from 25 weeks gestation and continued until delivery will reduce vaginal/rectal group B streptococcus (GBS) colonization rates. Secondary aims include reduction of maternal and neonatal antibiotic exposure, and maternal vaginal and urinary tract infections.

450 healthy pregnant women receiving care from a regulated maternity care professional and registered at either St. Paul's or BC Women's Hospitals in Vancouver, British Columbia will be recruited. Women will be introduced to the study through posters and flyers and information from their maternity care provider. Women will be provided with verbal and written information on the study and provide written consent to participate before being entered into the study. Women will be entered into the study following initial screening to confirm their eligibility to participate in the study and then randomized to the intervention or control group.

Women randomized to the intervention group will receive a daily combination of one lozenge and two capsules of oral probiotic supplements comprised of three probiotic species; Lactobacillus rhamnosus and Lactobacillus reuteri (Urex Plus VCap-5) and Streptococcus salivarius K12 (Blis K12). The control arm will receive identical placebos administered using the same route and regimen as the active probiotic. Both groups will begin taking their daily study lozenges and capsules at 25 weeks gestation until delivery.

Five study-specific swabs will be collected, three vaginal/rectal and two oral swabs. The first vaginal/rectal swab and the first oral swab will be obtained at intake, after randomization and prior to the start of the intervention. The second vaginal/rectal swab will be obtained at mid-point, between 29-33 weeks gestational age. The third vaginal/rectal swab and second oral swab will be collected between 35 weeks and delivery.

The primary outcome will be vaginal/rectal GBS status, ascertained from the last study-specific vaginal/rectal swab. Statistical analysis will be on the basis of intention to treat. Treatment effect will be estimated using logistic regression. A two-tailed p-value <0.05 will be considered significant.

Secondary analysis will be performed on last observation moving forward, protocol-compliant groups and with adjustment for care-provider type and use of other dietary probiotic sources.

• Study Type: Interventional
• Enrollment (Actual): 168
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3N1
      • BC Women's Hospital
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • St. Paul's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Pregnant with a singleton
• Gestational age between 23 and 25+0 weeks
• Over the age of 18
• Registered for delivery, at one of the participating centres
• Under the care of a regulated maternity care provider (midwife, obstetrician (OB), or family physician).

Exclusion Criteria:

• Unable to provide consent
• Fetus has known major anomalies
• Significant immunosuppression
• Type I or Type II diabetes (non-gestational)
• Previous infant with GBS (these women will automatically be advised to be treated with IV antibiotic therapy)
• GBS bacteriuria diagnosed in present pregnancy (reasoning as per above)
• Plans to use oral or vaginal probiotic supplementation/therapy (capsules/tablets/lozenges/drinks) during their pregnancy (outside of natural food sources; yogurt, kimchi, kombucha etc)
• Enrolled in another study that involves the administration of a drug/product

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control; Placebo	Other: Placebo; Participants will be asked to take 2 placebo capsules and 1 placebo lozenge daily from 25 weeks pregnancy
Experimental: Intervention; Probiotic supplementation	Dietary supplement: Probiotic supplementation; Participants will take two capsules daily of Urex Plus VCap-5 (each containing 2.5 billion CFUs of L. rhamnosus and L. reuteri) and one lozenge of Blis K12 (1 billion CFUs of streptococcus Salivarius)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The primary outcome will be vaginal/rectal GBS colonization status at delivery	Measured using the study-specific rectal/vaginal swab	Last vaginal/rectal swab taken after 35 weeks gestation and prior to delivery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maternal antibiotic exposure	Women will be asked in each questionnaire if they have had any antibiotics prescribed and if so for the name of the antibiotic. Information will also be collected on antibiotics prescribed from medical records	Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
Maternal urinary tract infections	Women will be asked in each questionnaire if they have been diagnosed with a urinary tract infection and if so, if antibiotics were prescribed. Information will also be collected from medical records	Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
Maternal bacterial vaginosis infections	Women will be asked in each questionnaire if they have been diagnosed with bacterial vaginosis and if so, if treatment was prescribed. Information will also be collected from medical records	Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (6 weeks post-birth)
Maternal vaginal candida infections	Women will be asked in each questionnaire if they have been diagnosed with vaginal candida (yeast) infection and if so, if treatment was prescribed. Information will also be collected from medical records	Questionnaires administered at intake (22-25 weeks), mid-term (29-33 weeks), term (35-37 weeks) and chart review (4-6 weeks postpartum)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Infant birth weight	Recorded in medical records	Chart review at 4-6 weeks postpartum
Infant APGAR scores at 1, 5 and 10 minutes after birth	As recorded in medical records	Chart review at 4-6 weeks postpartum
(Direct) infant exposure to antibiotics	Recorded in medical records	Chart review at 4-6 weeks postpartum
Admission of infant to Neonatal Intensive Care Unit (NICU)	Recorded in medical records	Chart review at 4-6 weeks postpartum
Early onset neonatal infections, including GBS	Recorded in medical records	Chart review at 4-6 weeks postpartum
Passage of probiotic strains to gastrointestinal tract and vaginal epithelium and adherence	Presence of three probiotic strains (L. rhamnosus GR-1, L. reuteri RC-14, and S. salivarius K12) in swabs taken over the course of the study	Oral and vaginal/rectal swabs taken at 23-25 weeks, 29-33 weeks, and 35 weeks
Adverse events	From health care provider notification, participant notification, semi-weekly chart audits, participant questionnaires	From the time of randomisation to 28 days of discontinuing the study supplements
Maternal BMI	Recorded in medical records	Chart review at 4-6 weeks postpartum
Gestational diabetes	Recorded in medical records	Number of Participants with gestational diabetes recorded in chart review at 4-6 weeks postpartum
Pre-term labour	Recorded in medical records	Number of Participants with pre-term labour, recorded in chart review at 4-6 weeks postpartum
Pre-term and pre-labour rupture of membranes	Recorded in medical records	Number of Participants with pre-term and pre-labour rupture of membranes, recorded in chart review at 4-6 weeks postpartum
Chorio-amnionitis	Recorded in medical records	Number of Participants with chorio-amnionities, recorded in chart review at 4-6 weeks postpartum
Pre- and/or post-partum depression	Any diagnosis of pre- and/or post-partum depression, date of onset, duration and treatment prescribed recorded in medical records.	Number of Participants with pre- and/or post-partum depression, recorded in chart review at 4-6 weeks postpartum

Collaborators and Investigators

• Sponsor: University of British Columbia
• Collaborators: Dublin City University
• Investigators: Principal Investigator: Michelle M Butler, PhD, RM, Dublin City University; Principal Investigator: Patricia Janssen, PhD, UBC School of Population and Public Health

Publications and helpful links

General Publications

• Di Pierro F, Colombo M, Zanvit A, Risso P, Rottoli AS. Use of Streptococcus salivarius K12 in the prevention of streptococcal and viral pharyngotonsillitis in children. Drug Healthc Patient Saf. 2014 Feb 13;6:15-20. doi: 10.2147/DHPS.S59665. eCollection 2014.
• Bizzarro MJ, Dembry LM, Baltimore RS, Gallagher PG. Changing patterns in neonatal Escherichia coli sepsis and ampicillin resistance in the era of intrapartum antibiotic prophylaxis. Pediatrics. 2008 Apr;121(4):689-96. doi: 10.1542/peds.2007-2171.
• Cox LM, Blaser MJ. Antibiotics in early life and obesity. Nat Rev Endocrinol. 2015 Mar;11(3):182-90. doi: 10.1038/nrendo.2014.210. Epub 2014 Dec 9.
• de Vrese M. Health benefits of probiotics and prebiotics in women. Menopause Int. 2009 Mar;15(1):35-40. doi: 10.1258/mi.2009.009008.
• Glasgow TS, Young PC, Wallin J, Kwok C, Stoddard G, Firth S, Samore M, Byington CL. Association of intrapartum antibiotic exposure and late-onset serious bacterial infections in infants. Pediatrics. 2005 Sep;116(3):696-702. doi: 10.1542/peds.2004-2421.
• Hanson L, Vandevusse L, Duster M, Warrack S, Safdar N. Feasibility of oral prenatal probiotics against maternal group B Streptococcus vaginal and rectal colonization. J Obstet Gynecol Neonatal Nurs. 2014 May-Jun;43(3):294-304. doi: 10.1111/1552-6909.12308. Epub 2014 Apr 22.
• Elias J, Bozzo P, Einarson A. Are probiotics safe for use during pregnancy and lactation? Can Fam Physician. 2011 Mar;57(3):299-301.
• Money D, Allen VM; INFECTIOUS DISEASES COMMITTEE. The prevention of early-onset neonatal group B streptococcal disease. J Obstet Gynaecol Can. 2013 Oct;35(10):939-948. doi: 10.1016/S1701-2163(15)30818-5.
• Mueller NT, Whyatt R, Hoepner L, Oberfield S, Dominguez-Bello MG, Widen EM, Hassoun A, Perera F, Rundle A. Prenatal exposure to antibiotics, cesarean section and risk of childhood obesity. Int J Obes (Lond). 2015 Apr;39(4):665-70. doi: 10.1038/ijo.2014.180. Epub 2014 Oct 9.
• Ohlsson A, Shah VS. Intrapartum antibiotics for known maternal Group B streptococcal colonization. Cochrane Database Syst Rev. 2013 Jan 31;(1):CD007467. doi: 10.1002/14651858.CD007467.pub3.
• PHAC (2011) Steptococcus Agalactiae, Pathogen Safety Data Sheet. Public Health Agency of Canada. Available at: http://www.phac-aspc.gc.ca/lab-bio/res/psds-ftss/streptococcus-agalactiae-eng.php
• Stensballe LG, Simonsen J, Jensen SM, Bonnelykke K, Bisgaard H. Use of antibiotics during pregnancy increases the risk of asthma in early childhood. J Pediatr. 2013 Apr;162(4):832-838.e3. doi: 10.1016/j.jpeds.2012.09.049. Epub 2012 Nov 6.
• Juarez Tomas MS, Ocana VS, Nader-Macias ME. Viability of vaginal probiotic lactobacilli during refrigerated and frozen storage. Anaerobe. 2004 Feb;10(1):1-5. doi: 10.1016/j.anaerobe.2004.01.002.
• Reid G. Probiotic and prebiotic applications for vaginal health. J AOAC Int. 2012 Jan-Feb;95(1):31-4. doi: 10.5740/jaoacint.sge_reid.
• Kaewsrichan J, Peeyananjarassri K, Kongprasertkit J. Selection and identification of anaerobic lactobacilli producing inhibitory compounds against vaginal pathogens. FEMS Immunol Med Microbiol. 2006 Oct;48(1):75-83. doi: 10.1111/j.1574-695X.2006.00124.x.
• Ortiz L, Ruiz F, Pascual L, Barberis L. Effect of two probiotic strains of Lactobacillus on in vitro adherence of Listeria monocytogenes, Streptococcus agalactiae, and Staphylococcus aureus to vaginal epithelial cells. Curr Microbiol. 2014 Jun;68(6):679-84. doi: 10.1007/s00284-014-0524-9. Epub 2014 Jan 28.
• Pascual LM, Daniele MB, Ruiz F, Giordano W, Pajaro C, Barberis L. Lactobacillus rhamnosus L60, a potential probiotic isolated from the human vagina. J Gen Appl Microbiol. 2008 Jun;54(3):141-8. doi: 10.2323/jgam.54.141.
• Patras KA, Wescombe PA, Rosler B, Hale JD, Tagg JR, Doran KS. Streptococcus salivarius K12 Limits Group B Streptococcus Vaginal Colonization. Infect Immun. 2015 Sep;83(9):3438-44. doi: 10.1128/IAI.00409-15. Epub 2015 Jun 15.
• Ho M, Chang YY, Chang WC, Lin HC, Wang MH, Lin WC, Chiu TH. Oral Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 to reduce Group B Streptococcus colonization in pregnant women: A randomized controlled trial. Taiwan J Obstet Gynecol. 2016 Aug;55(4):515-8. doi: 10.1016/j.tjog.2016.06.003.
• Wickens KL, Barthow CA, Murphy R, Abels PR, Maude RM, Stone PR, Mitchell EA, Stanley TV, Purdie GL, Kang JM, Hood FE, Rowden JL, Barnes PK, Fitzharris PF, Crane J. Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001 may reduce the prevalence of gestational diabetes mellitus: a randomised controlled trial. Br J Nutr. 2017 Mar;117(6):804-813. doi: 10.1017/S0007114517000289. Epub 2017 Apr 3.
• Acikgoz ZC, Gamberzade S, Gocer S, Ceylan P. [Inhibitor effect of vaginal lactobacilli on group B streptococci]. Mikrobiyol Bul. 2005 Jan;39(1):17-23. Turkish.

Helpful Links

• OPSiP study website

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2020
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): December 31, 2024

Study Registration Dates

• First Submitted: December 7, 2017
• First Submitted That Met QC Criteria: January 21, 2018
• First Posted (Actual): January 23, 2018

Study Record Updates

• Last Update Posted (Actual): September 13, 2023
• Last Update Submitted That Met QC Criteria: September 11, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Pregnancy; Probiotics; Group B Streptococcus; GBS
• Other Study ID Numbers: H17-02189

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pending approval from the REC and once all final results have been published, de-identified data will be made available upon request for secondary use of data. Any proposed projects for secondary use must be approved by the study working group and the local REB.
• IPD Sharing Time Frame: After primary trial results have been accepted for publication
• IPD Sharing Access Criteria: Access criteria are de-identified data only and requires approval as stated above from the trial working group and local REB
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

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