Title: The clinical and cost-effectiveness of testing for Group B Streptococcus: a cluster randomised trial with economic and acceptability evaluations (GBS3)
Funder: Department of Health and Social Care

Abstract: BACKGROUND_x000D_ Group B Streptococcus (GBS) is a bacterium present in the vagina and lower gut of approximately 1 in 4 pregnant women. GBS can come and go throughout pregnancy and is usually symptomless, but may be passed to the baby around birth. Approximately one baby in every 1750 will develop a GBS infection within 7 days of birth. Most will recover, but each year in the UK about 40 babies die and 1 in 14 of the survivors will have a long-term disability._x000D_ Giving women in labour antibiotics through a drip into their veins reduces the risk of newborn babies developing GBS infection. Current UK practice is to offer antibiotics when the baby is at higher risk of developing the infection: if the birth is preterm, if GBS was detected during the current pregnancy, if the woman has a fever or previously had an infected baby. This “risk factor” screening is imperfect: some babies are missed, and many women with risk factors do not carry GBS but receive antibiotics unnecessarily. We need a method to identify women carrying GBS, so that only those carrying GBS receive antibiotics. A solution is “routine testing” of every pregnant woman, and offering antibiotics in labour to those who are carrying GBS. There are two methods we could use – one is to test about 3-5 weeks before the due date with a test that gives a result within 48 hours. The other is to use a new rapid test done when the woman is in labour. Both tests have advantages and disadvantages._x000D_ _x000D_ AIMS OF THE RESEARCH_x000D_ To establish whether “routine testing” women (in late pregnancy or during labour), to direct the offer of antibiotics in labour, is better at reducing GBS infection in newborn babies than using the current “risk factor” approach, and whether it represents value for money for the NHS._x000D_ _x000D_ DESIGN AND METHODS USED_x000D_ We will work with 65 hospitals and birth centres. Hospitals will be randomly allocated to the “risk factor” or the “routine testing” approach. Hospitals allocated to the “routine testing” approach will be further randomly divided into testing women using a swab taken from the vagina and rectum either a) at 35-37 weeks of pregnancy, using a lab based test or b) in labour, using a rapid test machine. Women with a positive test result will be offered antibiotics in labour. All mothers in preterm labour or who had a previous baby with GBS infection will be offered antibiotics as per current guidance. _x000D_ _x000D_ We will compare the number of babies who develop serious infection born in all “routine testing” hospitals and birth centres with those using the “risk factor” approach. As infections are relatively rare, we will need to collect information on 320,000 women to be able to see a difference between the two main approaches. The allocated testing strategy will be adopted as standard practice by the unit, for which mothers will give standard verbal consent for the test. The data used in the trial will be routinely collected data retrieved from NHS databases. As such, individual written consent for participation in trial will not be sought. _x000D_ _x000D_ We will also interview women and healthcare professionals about the acceptability of the testing approaches (Written informed consent will be obtained for the interviews). Finally, we will compare the overall costs of each strategy and work out which represents the best value for money for the NHS. _x000D_ _x000D_ _x000D_ _x000D_ PATIENT AND PUBLIC INVOLVEMENT_x000D_ This study is supported by Group B Strep Support, the national charity working to prevent GBS infections, and by the National Childbirth Trust._x000D_ _x000D_ DISSEMINATION_x000D_ This project will provide the NHS with the evidence required to decide whether GBS “routine testing” should be implemented in the UK. Group B Strep Support and the National Childbirth Trust will use their extensive network of social and mainstream media connections to publicise the results.

Lay abstract: RESEARCH QUESTION_x000D_ Does “routine testing” of women for GBS colonisation in late pregnancy OR labour reduce the occurrence of early-onset neonatal sepsis, compared to the current “risk factor“ based strategy?_x000D_ _x000D_ BACKGROUND_x000D_ The UK National Screening Committee (NSC) does not recommend “routine testing” for GBS due to the absence of randomised data on either clinical or cost-effectiveness._x000D_ _x000D_ METHODS_x000D_ DESIGN: A multi-centre prospective two-arm parallel cluster randomised, superiority trial, with an internal pilot and feasibility evaluation and parallel economic modelling. Data will come from NHS Digital, National Neonatal Research Database, Health Episode Statistics and Public Health England, or devolved nation equivalents._x000D_ _x000D_ SETTING: 65 maternity units in England, Scotland, Wales._x000D_ _x000D_ STUDY POPULATIONS: All women who experience labour or prelabour rupture of membranes, at any gestational age =24 weeks. Purposive sampling of women and health care professionals for qualitative study. _x000D_ _x000D_ SCREENING STRATEGIES_x000D_ Primary comparison: “risk-factor” directed strategy (current practice) or a “routine testing” strategy._x000D_ Sub-randomisation of “routine testing” strategies: Intrapartum testing at greater than 37 weeks of vaginal-rectal swab with the GBS GeneXpert rapid test, or antenatal testing of veginal-rectal swab at 35-37 weeks with enrichment culture._x000D_ _x000D_ PRIMARY OUTCOME: All-cause early neonatal sepsis: either culture-positive (blood or cerebrospinal fluid) or negative/ unknown culture status with =3 agreed clinical signs or symptoms, for which antibiotics are given for =5 days, within 7 days of birth._x000D_ _x000D_ SECONDARY OUTCOMES:_x000D_ Neonatal: _x000D_ Birth weight, perinatal mortality, 5 minute Apgar, gestational age at birth, fetal acidaemia, neonatal specialist care (length of stay, highest level of care), seizures, abnormal neurological signs at >24 hours of age (hypotonia or abnormal level of consciousness)._x000D_ _x000D_ Maternal: Mode of onset of labour, mode of delivery, duration of hospital stay, change of intended location of childbirth, maternal intrapartum anaphylaxis._x000D_ _x000D_ Process: Maternal risk factors for EOGBS infection developing in baby, testing coverage, testing at appropriate time, test result available at least 4 hours before childbirth, GBS-specific IAP coverage, timing of IAP, number of doses of IAP, proportion of women who tested negative, positive or had no test, identified maternal risk factors at all sites, declines and acceptances of IAP, number of babies of mothers who tested positive for GBS and had IAP commenced, observation time following positive GBS result, maternal intrapartum or postnatal sepsis. _x000D_ _x000D_ Economic: Incremental cost per case of early neonatal sepsis avoided as a result of alternative testing strategies for GBS in pregnancy or labour, incremental cost per quality adjusted life year gained associated with each strategy, as a result alternative testing strategies for GBS in pregnancy or labour._x000D_ _x000D_ Qualitative: Acceptability, barriers and facilitators to implementation, and on the influence of site-specific context and process mechanisms on GBS testing._x000D_ _x000D_ SAMPLE SIZE_x000D_ 320,000 women accrued over 3 years from 65 units will enable detection of a 40% relative reduction in the primary outcome of early-onset neonatal sepsis with 90% power._x000D_ _x000D_ TIMELINES FOR DELIVERY_x000D_ Milestone completed_x000D_ Collaboration agreements in place. Protocol development. Sites identified._x000D_ Favourable ethical opinion. Access to routine data sources gained. Training packages developed. Database and data collection tools produced, statistical analysis plan generated. _x000D_ Sites open and testing according to allocation, 100 individual-level datasets collected, database populated, acceptability data analysed._x000D_ Future milestones_x000D_ Completion of accrual, completion of individual-level data, routine data retrieval._x000D_ Data analysis of RCT and economic evaluation, write-up of draft final report._x000D_ _x000D_ ANTICIPATED IMPACT AND DISSEMINATION_x000D_ This project will provide the National Screening Committee with the evidence required to decide whether universal GBS screening should be implemented in the UK. GBS Support and the National Childbirth Trust will use their extensive network of social and mainstream media connections to disseminate the results.

Research activity codes: 6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFECTION;REPRODUCTIVE HEALTH AND CHILDBIRTH