Detecting Group B Streptococcus bacterial infection in the womb before labour
| ISRCTN | ISRCTN84271915 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN84271915 |
| IRAS number | 316414 |
| Secondary identifying numbers | IRAS 316414, CPMS 53745 |
- Submission date
- 08/09/2022
- Registration date
- 06/10/2022
- Last edited
- 27/01/2025
- Recruitment status
- Recruiting
- Overall study status
- Ongoing
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
A bug (bacterium) known as GBS (Group B Streptococcus) is present in the birth canal in about 1 in 5 pregnant women. In 2019, we demonstrated that GBS can get into the womb before labour starts and we can find it in the placenta. We now want to study a large number of women being delivered by planned caesarean section. Studying samples from women attending a planned caesarean section means we can be sure that any bugs we find invaded the womb before labour starts. We will ascertain how many women have GBS in the placenta before labour. We will ascertain how the placenta and the baby respond to the presence of GBS. We will ascertain whether anything about the specific type of GBS present in the mother determines whether or not it can invade the womb. During the study, we will provide anonymous patient samples of umbilical cord blood and placenta to biobanks that can be accessed by researchers in other fields who also want to study tissues obtained at the time of planned caesarean birth.
Who can participate?
Women undergoing an elective caesarean section prior to the onset of labour or membrane rupture
What does the study involve?
In the operating theatre, the treatment will be exactly the same as normal, but with the following additions. First, we will obtain a maternal blood sample prior to the caesarean section. If possible, this will be obtained by the anaesthetist when they insert an intravenous line (cannula). However, the woman can decline to have this sample taken. Second, a midwife always passes a catheter into the bladder before a caesarean section. If consent is provided to the study, they will also briefly (seconds) insert a swab into the lower vagina and a swab into the back passage (rectum) to check for the presence of the GBS bug. This is usually done after the anaesthetic (usually a regional block) hence the woman should not feel any discomfort. Women have the option to check a box on the consent form stating that they want to opt-out of those procedures. Third, when the surgeon is about to deliver the baby they will obtain a sample of the fluid from around the baby and we will check this for the presence of the GBS bug. Finally, when the surgeon delivers the placenta, it will be passed on to the research team who will obtain further samples.
What are the possible benefits and risks of participating?
There are no potential benefits for the participant personally. But if we can understand more about how GBS affects the baby it may help other women and their babies in the future. There are no risks to the mother or baby from participating.
Where is the study run from?
The Rosie Hospital, Cambridge (United Kingdom)
When is the study starting and how long is it expected to run for?
September 2021 to November 2026
Who is funding the study?
Medical Research Council (United Kingdom)
Who is the main contact?
Prof GCS Smith (United Kingdom)
gcss2@cam.ac.uk
Contact information
Principal Investigator
Department of Obstetrics and Gynaecology
University of Cambridge
Box223
The Rosie Hospital
Robinson Way
Cambridge
CB2 0SW
United Kingdom
 ORCID ID |
0000-0003-2124-0997 |
|---|---|
| Phone | +44(0)1223 336871 |
| gcss2@cam.ac.uk |
Study information
| Study design | Single-centre cohort observational study |
|---|---|
| Primary study design | Observational |
| Secondary study design | Cohort study |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific title | Pre-labour invasion of the human uterus by Streptococcus agalactiae |
| Study acronym | DIGS |
| Study objectives | Vertical transmission of Group B Streptococcus (GBS) during labour and delivery is the major determinant of early neonatal death due to sepsis. We previously reported that GBS was the only bacterial DNA signal detectable in the placenta prior to labour onset. We hypothesise that: 1. Invasion of the uterus by group B Streptococcus (GBS): The risk of GBS being present in the intra-uterine tissues prior to membrane rupture and labour onset is increased among women with GBS genital tract colonisation 2. GBS and fetal inflammatory response syndrome: Pre-labour invasion of the uterus by GBS is associated with a fetal inflammatory response and predisposes the infant to neonatal morbidity 3. GBS genomics The genome of GBS colonising the mother determines the risk of intrauterine invasion |
| Ethics approval(s) | Approved 03/11/2022, East of England - Essex Research Ethics Committee (The Old Chapel, Royal Standard Place, Nottingham, NG1 6FS, UK; +44 (0)207 1048106; NRESCommittee.EastofEngland-Essex@nhs.net), ref: 22/EE/0175 |
| Health condition(s) or problem(s) studied | Group B Steptococcus agalactiae infection |
| Intervention | We will quantify GBS DNA in the placenta, fetal membranes, amniotic fluid, and fetal blood from ~1,800 women being delivered by pre-labour caesarean section and compare the proportion of GBS-positive samples in women with and without GBS colonisation. We will then compare levels of inflammatory mediators in all four sample types in relation to the presence or absence of GBS DNA, and the risk of neonatal morbidity in those with and without GBS DNA in the intra-uterine tissues. Among women colonised by GBS, we will test associations between intra-uterine invasion by GBS and whole genome sequencing (WGS) of the isolates cultured from the mother. Specifically, we will compare previously described virulence factors (e.g. hyper-virulent adhesin) and we will perform discovery-based, hypothesis-generating analyses of the WGS data. Finally, we will perform Bayesian network analysis to determine causal associations and interactions between maternal, pathogen, and inflammatory factors, and to adjust associations for the effects of potential maternal confounders. |
| Intervention type | Other |
| Primary outcome measure | 1. Admission of the neonate for special or intensive care since delivery due to the main diagnosis of confirmed or suspected sepsis measured using electronic medical records at the time of hospital discharge following delivery 2. Presence of group B Streptococcus (GBS) in fresh intra-uterine tissue samples (placenta, placental membranes, amniotic fluid, umbilical cord blood) and rectal and vaginal swabs detected by culture following delivery. Using current practices, samples will be incubated in Todd-Hewitt broth supplemented with antibiotics to select for GBS. After culture, identification of GBS will be confirmed using matrix-assisted laser desorption/ionisation time-of-flight (MALDI-TOF) mass spectrometry. Antibiotic disc susceptibility testing will be performed according to EUCAST guidelines. The presence of GBS DNA will be identified using PCR-qPCR for the bacterial 16S rRNA gene on frozen samples of the placenta, fetal membranes, fetal blood and amniotic fluid. 3. Presence of inflammation in the placenta and umbilical cord will be determined in frozen samples obtained at the time of delivery. Pro-inflammatory cytokines (IL-6, IL-8, TNF-α and IL-1β ) will be measured using the R&D Systems Ella Automated Immunoassay platform. The levels of inflammatory cytokines will be compared between cases where GBS was detected with GBS-negative controls. |
| Secondary outcome measures | Neonate outcome: 1. Apgar score measured according to APGAR scoring system at 1,5 and 10 minutes after delivery. Data obtained from electronic medical records. 2. Hypoxic ischaemic encephalopathy, defined as any diagnosis of hypoxic-ischaemic encephalopathy prior to discharge. Data obtained from electronic medical records following discharge. 3. Any invasive or non-invasive ventilation that was required prior to discharge from the hospital. Data obtained from electronic medical records following discharge 4. Any use of inotropes prior to discharge from the hospital. Data obtained from electronic medical records following discharge. 5. Length of stay in neonatal intensive care unit or special care baby unit. Determined following discharge by reviewing electronic medical records. Maternal outcome: 1. Maternal post-delivery haemorrhage, defined as a blood loss greater than 500 ml during their Caesarean section. Data obtained from electronic medical records. 2. Infection (e.g. endometritis). Defined as a temperature > 38oC or clinically treated for infection following caesarean section, determined by review of electronic medical records following discharge 3. Positive microbiology cultures for GBS (urine, high vaginal swab, placenta) during or after pregnancy. Determined by review of electronic medical records following discharge from hospital. |
| Overall study start date | 01/09/2021 |
| Completion date | 01/11/2026 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 17 Years |
| Sex | Female |
| Target number of participants | 1800 |
| Key inclusion criteria | Patients planned for caesarean delivery at the Rosie Hospital Cambridge, prior to the onset of labour or membrane rupture |
| Key exclusion criteria | 1. Unable to consent 2. Aged 16 years old and under 3. Antibiotic treatment within the preceding week 4. An infectious condition which could represent a hazard (e.g. high-risk carrier of viral hepatitis B) |
| Date of first enrolment | 15/12/2022 |
| Date of final enrolment | 01/12/2025 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centre
Cambridge
CB2 0QQ
United Kingdom
Sponsor information
Hospital/treatment centre
Hills Road
Cambridge
CB2 0QQ
England
United Kingdom
| Phone | +44 (0)1223 349302 |
|---|---|
| research@addenbrookes.nhs.uk | |
| Website | https://www.cuh.org.uk/ |
"ROR" |
https://ror.org/04v54gj93 |
University/education
The Old Schools
Trinity Ln
Cambridge
CB2 1TN
England
United Kingdom
| Phone | +44 (0)1223 337733 |
|---|---|
| not@provided.com | |
| Website | https://www.cam.ac.uk/ |
|
"ROR" |
https://ror.org/013meh722 |
Funders
Funder type
Research council
Government organisation / National government
- Alternative name(s)
- Medical Research Council (United Kingdom), UK Medical Research Council, MRC
- Location
- United Kingdom
Results and Publications
| Intention to publish date | 01/12/2026 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Data will be available in relation to the studies described above (i.e. demographic, clinical and laboratory). Data will be available for sharing 4 years after the first recruitment of a patient (approximately November 2026) and should continue to be available until August 2032. Requests should be sent to Prof GCS Smith and reasonable requests with an acceptable scientific case will be considered. Transfer of data will require a Data Transfer Agreement (DTA), with the signature of the requester and a legal representative of the institution. The DTA will specify all conditions of the agreement and the scope of the work and will be negotiated by the Research Operations Office of the University of Cambridge. Participant identifiers will not be included in the data sent and researchers will be required to provide a commitment to refrain from using the data to try and identify participants. All participants have provided their written informed consent for their data to be used in this way. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Protocol file | version 2 | 21/09/2022 | 13/12/2022 | No | No |
| HRA research summary | 28/06/2023 | No | No |
Additional files
Editorial Notes
27/01/2025: The recruitment start date was changed from 01/12/2022 to 15/12/2022.
13/12/2022: The following changes were made to the trial record:
1. The ethics approval was added.
2. Uploaded protocol (not peer-reviewed) as an additional file.
01/11/2022: Internal review.
28/09/2022: Trial's existence confirmed by the Medical Research Council (UK).
