Group B Streptococcal Infection Clinical Trial
Official title:
Effect of Probiotics on GBS Colonization Status During Pregnancy: A Pilot Randomized Controlled Trial
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.
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.
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