Effect of Probiotics on GBS Colonization Status During Pregnancy: A Pilot Randomized Controlled Trial
Condition: Group B Streptococcal Infection
MeSH terms: Streptococcal Infections
Study type: Interventional

Summary: 
      Group B Streptococcus (GBS) is the leading cause of neonatal morbidity and mortality in
      Canada. It may be passed from a study participant colonized in the genital tract by GBS to
      their baby during vaginal birth. While approximately 10 to 30% of pregnant people harbour GBS
      in the vagina or rectum, the incidence of neonatal GBS disease is 1 to 2 infants per 1000
      births. The use of intrapartum antibiotics to treat colonized individuals with or without
      risk factors has led to a 70% decline in the incidence of early-onset GBS sepsis in the past
      decade. Despite this impressive decline, antibiotic resistance has become a major public
      health concern. Association between intrapartum antibiotic use and ampicillin resistance in
      E. coli isolated from neonates has previously been documented. Furthermore, while GBS has
      remained sensitive to penicillin, 20% are resistant to erythromycin and clindamycin, which
      are alternate drugs for patients allergic to penicillin. Alternative approaches are therefore
      needed to reduce the risk of GBS infection.

      We therefore propose to study the use of Lactobacillus rhamnosus GR-1 and Lactobacillus
      reuteri RC-14 (Lactobacillus fermentum RC-14) in the colonization status of GBS in pregnant
      people. Lactobacilli are part of normal gut and vaginal flora and have been widely used as
      probiotics to treat various conditions. In particular, these two strains have shown to be
      beneficial in the treatment of urinary tract infections and bacterial vaginosis. Our study
      design involves recruiting two hundred pregnant people (one hundred in each arm) through
      various midwifery practices in the GTA at the end of their first trimester of pregnancy.
      These individuals will be randomized to receive probiotics or placebo for twelve weeks of
      their pregnancies and will be cultured before delivery to determine their colonization
      status. The capsules with probiotics and placebo will be provided free of charge. The study
      design was chosen to minimize the cost and clients' visits to the clinic as vaginal/rectal
      swabs are routinely offered at 35-37 weeks of gestation.
    

Detailed description: 
      Study Abstract

      Group B Streptococcus (GBS) is the leading cause of neonatal morbidity and mortality in
      Canada. It may be passed from a study participant colonized in the genital tract by GBS to
      their baby during vaginal birth. While approximately 10 to 30% of pregnant people harbour GBS
      in the vagina or rectum, the incidence of neonatal GBS disease is 1 to 2 infants per 1000
      births. The use of intrapartum antibiotics to treat colonized individuals with or without
      risk factors has led to a 70% decline in the incidence of early-onset GBS sepsis in the past
      decade. Despite this impressive decline, antibiotic resistance has become a major public
      health concern. Association between intrapartum antibiotic use and ampicillin resistance in
      E. coli isolated from neonates has previously been documented. Furthermore, while GBS has
      remained sensitive to penicillin, 20% are resistant to erythromycin and clindamycin, which
      are alternate drugs for patients allergic to penicillin. Alternative approaches are therefore
      needed to reduce the risk of GBS infection.

      We therefore propose to study the use of Lactobacillus rhamnosus GR-1 and Lactobacillus
      reuteri RC-14 (Lactobacillus fermentum RC-14) in the colonization status of GBS in pregnant
      people. Lactobacilli are part of normal gut and vaginal flora and have been widely used as
      probiotics to treat various conditions. In particular, these two strains have shown to be
      beneficial in the treatment of urinary tract infections and bacterial vaginosis. Our study
      design involves recruiting two hundred pregnant people (one hundred in each arm) through
      various midwifery practices in the GTA at the end of their first trimester of pregnancy.
      These individuals will be randomized to receive probiotics or placebo for twelve weeks of
      their pregnancies and will be cultured before delivery to determine their colonization
      status. The capsules with probiotics and placebo will be provided free of charge. The study
      design was chosen to minimize the cost and clients' visits to the clinic as vaginal/rectal
      swabs are routinely offered at 35-37 weeks of gestation.

      As lactobacilli are part of the human gut flora and have low pathogenicity, no adverse
      reaction to lactobacilli or placebo is anticipated, though some clients may experience
      flatulence. The process of reporting unexpected or adverse events is outlined in the Case
      Report Form (CRF). Concerns relating to the integration of this study into the practices of
      midwives in the community will be mitigated by letters of information to midwives and
      clients, informed choice discussions between the researchers and study participants, and
      letters of consent.

      Background

      Group B Streptococcus (GBS) is a gram-positive bacterium. The gut is the bodily reservoir for
      GBS, and the most likely source of vaginal colonization. While part of the normal vaginal
      flora and usually of no noticeable consequence to people, GBS emerged in the 1970s as the
      leading cause of neonatal morbidity and mortality. A primary risk factor for neonatal
      contraction is colonization of the carrier's vaginal tract, with the bacteria being passed to
      the baby as it travels through the birth canal, or by being spread to the amniotic fluid.
      This vertical transmission can lead to early-onset GBS disease of the newborn (EOGBSD), which
      manifests in the first 7 days of life, and can be fatal. Therefore, current clinical
      recommendations focus on the prevention of GBS-associated diseases by monitoring and managing
      the GBS colonization status of the pregnant person in an attempt to reduce the probability of
      the neonate contracting a GBS infection during birth. Currently, midwives in Ontario are
      advised to offer all clients culture screening for GBS at 35-37 weeks gestation. People who
      screen positive for GBS are to be offered intrapartum antibiotic prophylaxis (IAP) either
      universally, or based on other risk factors. IAP is not specifically recommended for who can
      reasonably be expected to be GBS-free (i.e. screened negative for GBS when tested at 35-37
      weeks).

      While EOGBSD is potentially very serious, the use of IAP is associated with its own risks.
      Concomitant with the use of IAP are the risks of: maternal anaphylaxis, emergence of
      antibiotic-resistant strains of bacteria, infection with non-GBS organisms, colonization with
      yeast, the development of allergies and asthma. In addition, because IAP requires clients to
      labour attached to an IV at various time-points throughout their labour, IAP is a disruption
      to the natural course of labour and delivery that midwives try to facilitate. Furthermore,
      GBS screening and positive status can be very stressful for people. Therefore, in an attempt
      to eliminate stress, the need for IAP and the risks and inconvenience associated with it,
      midwives offer certain strategies to clients in an attempt to reduce the probability that
      they will screen positive for the GBS bacteria. Homeopathy, garlic suppositories, and
      probiotic capsules are all methods midwives and their clients use in an attempt to prevent
      vaginal colonization by GBS. However, there is no evidence to support or refute the use of
      these remedies.

      Probiotics are defined as viable microbial food supplements which, if given in adequate
      quantities, confer a health benefit to the host. Bacteria of the lactobacillus sp. are the
      most common in probiotic capsule preparations, and they are also the most common type of
      organism found in the natural vaginal flora. The natural vaginal flora play an important role
      in dislodging and inhibiting pathogens. The rationale for the use of probiotics then, is the
      return of the vaginal flora to their healthy, natural state. Indeed, probiotics have been
      shown to alter the vaginal flora being an effective supplement in the treatment and cure of
      bacterial vaginosis, and vulvovaginal yeast infections. Probiotic capsules are considered
      safe for use in pregnancy.

      Research Question

      Does taking probiotics for 12 weeks during pregnancy effect the GBS colonization status of
      people at 35-37 weeks of pregnancy?

      Study Design

      Probiotic Capsules

      L. rhamnosus GR-1 and L. reuteri RC-14 will be supplied to pregnant people in gelatin
      capsules containing 2.5 billion viable cells of each strain (CFU). These organisms have been
      previously shown to colonize the vagina after being taken orally and displace the pathogens
      causing bacterial vaginosis and vaginal yeast infections, and have been shown to be an
      effective treatment, or accessory to treatment of these conditions. This formulation has been
      previously approved for use in clinical trials in Canada. The probiotics and placebo are
      provided in gelatin capsules. The use of gelatin capsules may be prohibitive for some
      individuals who are vegetarian, vegan, Muslim or Jewish.

      Subjects & Randomization

      This is a randomized, placebo-controlled trial. In order to achieve 80% statistical power and
      a p value of 0.05 with the assumption that 20% of people in the placebo group will become GBS
      positive, 200 clients will be recruited from participating midwifery clinics in the Greater
      Toronto Area and randomized into each study arm (2 groups of 100). Clients will be offered
      entry to the study upon beginning midwifery care, and will be provided with either oral
      Lactobacillus GR-1 and RC-14 or placebo (cellulose, magnesium stearate). Two capsules are to
      be taken once daily for 12 weeks from 24 weeks of pregnancy until their GBS swab test which
      is taken at 35-37 weeks of pregnancy, routine to the standard of midwifery care.

      Relevance

      The hope is that this study will shed some light on the utility of probiotics in midwifery
      care as pertaining to GBS colonization. This study may provide evidence that probiotic
      prophylaxis is an effective, low-risk strategy that we can continue to offer to clients to
      reduce their risk of GBS colonization and thus, the need for IAP and the risks and
      inconvenience associated with it. Alternatively, this study will provide evidence that
      probiotics are not an efficacious supplement to offer, and should not be recommended, as the
      capsules are quite costly and their purchase, or the decision-making process around whether
      they can or should obtain capsules, may place undue hardship on some people.

      Safety and Adverse Event Monitoring

      It is the investigators mandate to protect the safety of the study participants. The
      possibility of adverse events through the use of placebo and probiotics is extremely minimal.
      Participants are informed that there is a small chance of experiencing flatulence with the
      capsules. Any unexpected or adverse events will be reported immediately by participants to
      their midwife, who will document it on the Case Report Form (CRF) and will notify the
      Practice Research Collaborator (PRC) at their clinic. The PRC then would notify the PI or
      their delegate for further investigation. As study participants are all in the direct care of
      midwives who are aware of the study and their client's participation in the study, midwives
      will manage, consult, or transfer care according to their College guidelines in the event of
      an unexpected or adverse event. The PRC and PI or their delegates are responsible for
      documenting any AEs in the CRF. The PI, in collaboration with the QI and Co-I, where
      applicable, will determine the severity of the AE and causality. Severe AEs are reportable to
      the REB and Health Canada. Study participants who experience unexpected, adverse, or severe
      adverse events will be considered for exclusion from the study.
    

Intervention name(s): Probiotic; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Lactobacillus GR-1 and RC-14
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: GBS; Probiotics; Group B Streptococcal; Pregnancy