The aim of the GBS2 trial was to establish whether or not, a strategy of targeted IAP based on the results of a rapid intrapartum test for maternal GBS colonisation can reduce unnecessary maternal and neonatal antibiotic exposure in women with risk factors for their babies developing early-onset GBS disease, and if the rapid test can accurately diagnose GBS colonisation in clinical practice.
Primary objectives
- To determine if the use of the rapid intrapartum test for maternal GBS colonisation reduces maternal and neonatal antibiotic exposure, compared with usual care in which IAP is based on maternal risk factors, in a cluster randomised trial.
- To determine the real-time accuracy of the rapid intrapartum test for GBS colonisation among women in labour with risk factors for GBS transmission, compared with the reference standard of selective enrichment culture, in a cross-sectional study nested within the randomised cohort.
Secondary objectives
- To evaluate if the rapid intrapartum test reduces IAP in the mother for any indication compared with usual care.
- To evaluate the effect of the rapid test, compared with the usual-care strategy, on neonatal exposure to antibiotics, neonatal morbidity and neonatal mortality.
- To evaluate if timely IAP administration can be achieved with a rapid intrapartum test to ensure adequate antibiotic exposure by establishing a standard operating procedure for use of the test.
- To evaluate the cost and cost-effectiveness of using the rapid intrapartum test compared with usual care.
- To evaluate the antibiotic resistance profile of GBS and the colonisation by other antibiotic-resistant bacteria of the mother from the intrapartum vaginal/rectal swab, and the risk of such colonisation in the baby at 6 weeks of age.
- To evaluate the colonisation rate of antibiotic-resistant bacteria, particularly E. coli, MRSA and vancomycin-resistant enterococci (VRE), in vaginal/rectal samples from women.
- To evaluate the extent to which colonisation of specific resistant bacteria or resistance elements of the mother at the time of birth increase the risk of carriage of those specific bacteria or elements to the infant at 6 weeks of postnatal age.
- To gather some information on peripartum risk factors for transmission (e.g. mode of birth, gestational age and antibiotic exposure).
Rationale for trial design
A randomised comparison provides the most reliable data to compare test strategies for IAP to prevent early-onset GBS infection. It was decided that individual randomisation would not be feasible for the GBS2 trial because of two factors. First, if a GeneXpert system is available on a maternity ward, given its presumed high accuracy, it would be difficult and potentially unethical not to offer this test to all women in labour. Second, women would have to provide consent at the point of diagnosis of labour. The first GBS study51 showed that obtaining consent for research delays the start of the testing process and inevitably means that many women are not approached by midwives for participation. This undermines the principle that it is the strategy of targeted testing being compared and, hence, is not generalisable at the population level.
The cluster trial randomised different maternity units to follow either the rapid testing or the usual-care strategy of offering IAP to all women with risk factors, and required that all women with risk factors followed the same strategy within each unit. In cluster trials, it is important that either all eligible participants are identified prior to the unit being randomised, which is possible with a prevalent population, or outcome data from all eligible participants are included in the analysis. As intrapartum risk factors can be identified only at the time when the screening strategy needs to be applied, it was necessary to include all women with risk factors in the analysis. If consent was sought, there would be selection by midwife (overtly or unintentionally, because of time pressures) and resulting in women declining to provide swabs or data for research. The selection bias caused by the need to approach and individually consent participants within a cluster leads to unreliable estimates of screening effectiveness.52 However, if the testing strategy is adopted as standard practice by the maternity unit and anonymous routinely collected data are retrieved, consent for research is unnecessary (although clinical consent for vaginal/rectal and neonatal swabs would prevail).
For the test to be proven useful, it will need to detect a higher proportion of GBS maternal carriage than other tests, but not at the cost of low specificity and overuse of IAP. The appropriate evaluation of the test’s performance was to follow a classic test accuracy design. The rapid test performed on intrapartum rectovaginal swabs was the index test, which was compared with microbiological culture of duplicate swabs serving as the reference standard. The a priori sample size was computed to determine the sensitivity of the rapid test within a 10% margin, but with the ability to assess specificity with greater precision.
If a rapid POC test improves the detection of maternal GBS colonisation in the intrapartum period, then it is likely that important cost implications will be seen for the health-care sector. For example, IAP will be avoided for many women who test negative and appropriate treatment for those who test positive should lead to a reduction in admission to neonatal intensive care. The accuracy of the test must be carefully examined and established for its impact on both false-positive and false-negative results, and the costs and outcomes that follow based on decisions made as a result of the test must be evaluated. For example, the rapid test may detect additional cases of maternal GBS colonisation compared with the usual-care risk factor-based strategy, which will increase the use of antibiotics prescribed in the intrapartum period; however, it could ultimately reduce the risk of early-onset GBS infection and avoid costly neonatal admissions. Alternatively, replacement of the risk factor-based strategy with the rapid test may lead to an increased number of false positives, resulting in the administration of unnecessary IAP, or it could lead to an increased number of false-negative test results and consequential adverse outcomes.
This trial provided an opportunity to correlate maternal carriage of resistant bacteria with early colonisation of the corresponding infant. Maternal vaginal/rectal samples collected for the trial and used for the enrichment culture reference standard, and neonatal swabs and routinely collected specimens, were reprocessed to determine the presence of antibiotic-resistant Gram-negative bacteria, focusing particularly on ESBL-producing strains using selective media. Strains isolated from mothers and their infants were typed to determine the degree of relatedness. The outcomes from this part of the trial include the carriage rates of antibiotic-resistant Gram-negatives in the trial population of pregnant women, the risk of colonisation in their infant(s) and the peripartum risk factors for transmission (e.g. mode of birth, maternal comorbidities and colonising species).
An overall trial schema for the GBS2 trial is shown in Figure 2.
FIGURE 2 Overall trial schema for the GBS2 trial. AMR, antimicrobial resistance. (Figure not reproduced here; see the original article.)