A rapid intrapartum test for group B Streptococcus to reduce antibiotic usage in mothers with risk factors: the GBS2 cluster RCT.

BACKGROUND Mother-to-baby transmission of group B Streptococcus (Streptococcus agalactiae) is the main cause of early-onset infection. OBJECTIVES We investigated if intrapartum antibiotic prophylaxis directed by a rapid intrapartum test reduces maternal and neonatal antibiotic use, compared with usual care (i.e. risk factor-directed antibiotics), among women with risk factors for vertical group B Streptococcus transmission, and examined the accuracy and cost-effectiveness of the rapid test. DESIGN An unblinded cluster randomised controlled trial with a nested test accuracy study, an economic evaluation and a microbiology substudy. SETTING UK maternity units were randomised to either a strategy of rapid test or usual care. PARTICIPANTS Vaginal and rectal swabs were taken from women with risk factors for vertical group B Streptococcus transmission in established term labour. The accuracy of the GeneXpert® Dx IV GBS rapid testing system (Cepheid, Maurens-Scopont, France) was compared with the standard of selective enrichment culture in diagnosing maternal group B Streptococcus colonisation. MAIN OUTCOME MEASURES Primary outcomes were rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection and accuracy estimates of the rapid test. Secondary outcomes were maternal antibiotics for any indication, neonatal antibiotic exposure, maternal antibiotic duration, neonatal group B Streptococcus colonisation, maternal and neonatal antibiotic resistance, neonatal morbidity and mortality, and cost-effectiveness of the strategies. RESULTS Twenty-two maternity units were randomised and 20 were recruited. A total of 722 mothers (749 babies) participated in rapid test units and 906 mothers (951 babies) participated in usual-care units. There were no differences in the rates of intrapartum antibiotic prophylaxis for preventing early-onset group B Streptococcus infection in the rapid test units (41%, 297/716) compared with the usual-care units (36%, 328/906) (risk ratio 1.16, 95% confidence interval 0.83 to 1.64). There were no differences between the groups in intrapartum antibiotic administration for any indication (risk ratio 0.99, 95% confidence interval 0.81 to 1.21). Babies born in the rapid test units were 29% less likely to receive antibiotics (risk ratio 0.71, 95% confidence interval 0.54 to 0.95) than those born in usual-care units. The sensitivity and specificity of the rapid test were 86% (95% confidence interval 81% to 91%) and 89% (95% confidence interval 85% to 92%), respectively. In 14% of women (99/710), the rapid test was invalid or the machine failed to provide a result. In the economic analysis, the rapid test was shown to be both less effective and more costly and, therefore, dominated by usual care. Sensitivity analysis indicated potential lower costs for the rapid test strategy when neonatal costs were included. No serious adverse events were reported. CONCLUSIONS The Group B Streptococcus 2 (GBS2) trial found no evidence that the rapid test reduces the rates of intrapartum antibiotic prophylaxis administered to prevent early-onset group B Streptococcus infection. The rapid test has the potential to reduce neonatal exposure to antibiotics, but economically is dominated by usual care. The accuracy of the test is within acceptable limits. FUTURE WORK The role of routine testing for prevention of neonatal infection requires evaluation in a randomised controlled trial. TRIAL REGISTRATION Current Controlled Trials ISRCTN74746075. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 12. See the NIHR Journals Library website for further project information.

[1]  P. Bossuyt,et al.  Rapid intrapartum test for maternal group B streptococcal colonisation and its effect on antibiotic use in labouring women with risk factors for early-onset neonatal infection (GBS2): cluster randomised trial with nested test accuracy study , 2022, BMC Medicine.

[2]  P. Bassett,et al.  Differential rates of group B streptococcus (GBS) colonisation in pregnant women in a racially diverse area of London, UK: a cross‐sectional study , 2019, BJOG : an international journal of obstetrics and gynaecology.

[3]  N. Goel,et al.  Screening for early onset neonatal sepsis: NICE guidance-based practice versus projected application of the Kaiser Permanente sepsis risk calculator in the UK population , 2019, Archives of Disease in Childhood: Fetal and Neonatal Edition.

[4]  A. Mellmann,et al.  “Enhanced acquisition of antibiotic-resistant intestinal E. coli during the first year of life assessed in a prospective cohort study” , 2019, Antimicrobial resistance and infection control.

[5]  M. Asaduzzaman,et al.  Fecal Colonization With Multidrug-Resistant E. coli Among Healthy Infants in Rural Bangladesh , 2019, Front. Microbiol..

[6]  C. Peckham,et al.  Modelling the effect of the introduction of antenatal screening for group B Streptococcus (GBS) carriage in the UK , 2019, BMJ Open.

[7]  M. Meehan,et al.  Group B streptococcal disease in UK and Irish infants younger than 90 days, 2014-15: a prospective surveillance study. , 2019, The Lancet. Infectious diseases.

[8]  T. Zaoutis,et al.  Management of Neonates Born at ≥35 0/7 Weeks’ Gestation With Suspected or Proven Early-Onset Bacterial Sepsis , 2018, Pediatrics.

[9]  B. Spellerberg,et al.  Group B Streptococcal Colonization, Molecular Characteristics, and Epidemiology , 2018, Front. Microbiol..

[10]  L. Logan,et al.  The Growing Threat of Antibiotic Resistance in Children. , 2018, Infectious disease clinics of North America.

[11]  J. Pereira,et al.  Diagnostic yield of real-time polymerase chain reaction in the diagnosis of intrapartum maternal rectovaginal colonization by group B Streptococcus: a systematic review with meta-analysis. , 2018, Diagnostic microbiology and infectious disease.

[12]  P. Brocklehurst,et al.  The incidence, characteristics, management and outcomes of anaphylaxis in pregnancy: a population‐based descriptive study , 2018, BJOG : an international journal of obstetrics and gynaecology.

[13]  S. Madhi,et al.  Infant Group B Streptococcal Disease Incidence and Serotypes Worldwide: Systematic Review and Meta-analyses , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[14]  S. Madhi,et al.  Maternal Colonization With Group B Streptococcus and Serotype Distribution Worldwide: Systematic Review and Meta-analyses , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[15]  S. Madhi,et al.  Preterm Birth Associated With Group B Streptococcus Maternal Colonization Worldwide: Systematic Review and Meta-analyses , 2017, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[16]  S. Schrag,et al.  Epidemiology of Invasive Early-Onset Neonatal Sepsis, 2005 to 2014 , 2016, Pediatrics.

[17]  W. Demczuk,et al.  Serotype Distribution, Population Structure, and Antimicrobial Resistance of Group B Streptococcus Strains Recovered from Colonized Pregnant Women , 2016, Journal of Clinical Microbiology.

[18]  Yuzhong Yan,et al.  Investigation of serotype distribution and resistance genes profile in group B Streptococcus isolated from pregnant women: a Chinese multicenter cohort study , 2016, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[19]  B. Giraudeau,et al.  Timeline cluster: a graphical tool to identify risk of bias in cluster randomised trials , 2016, British Medical Journal.

[20]  B. Mol,et al.  PROMISE: first-trimester progesterone therapy in women with a history of unexplained recurrent miscarriages - a randomised, double-blind, placebo-controlled, international multicentre trial and economic evaluation. , 2016, Health technology assessment.

[21]  K. Costeloe,et al.  ESBL-producing Enterobacteriaceae in 24 neonatal units and associated networks in the south of England: no clustering of ESBL-producing Escherichia coli in units or networks. , 2016, The Journal of antimicrobial chemotherapy.

[22]  K. Kimura,et al.  High isolation rate of MDR group B streptococci with reduced penicillin susceptibility in Japan. , 2015, The Journal of antimicrobial chemotherapy.

[23]  A. Ohlsson,et al.  Vaginal chlorhexidine during labour to prevent early-onset neonatal group B streptococcal infection. , 2014, The Cochrane database of systematic reviews.

[24]  J. Seale,et al.  Perinatal vertical transmission of antibiotic‐resistant bacteria: a systematic review and proposed research strategy , 2014, BJOG : an international journal of obstetrics and gynaecology.

[25]  G Kahlmeter,et al.  Development of the EUCAST disk diffusion antimicrobial susceptibility testing method and its implementation in routine microbiology laboratories. , 2014, Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases.

[26]  P. Sánchez,et al.  Prompt control of an outbreak caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae in a neonatal intensive care unit. , 2013, The Journal of pediatrics.

[27]  J. Campos,et al.  Outbreak of multidrug-resistant CTX-M-15-producing Enterobacter cloacae in a neonatal intensive care unit. , 2013, Journal of medical microbiology.

[28]  David Moher,et al.  Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement , 2013, Cost Effectiveness and Resource Allocation.

[29]  J. Schrenzel,et al.  Antibiotic resistance patterns among group B Streptococcus isolates: implications for antibiotic prophylaxis for early-onset neonatal sepsis. , 2013, Swiss medical weekly.

[30]  David Moher,et al.  Consolidated Health Economic Evaluation Reporting Standards (CHEERS)--explanation and elaboration: a report of the ISPOR Health Economic Evaluation Publication Guidelines Good Reporting Practices Task Force. , 2013, Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research.

[31]  K. Khan,et al.  Feasibility of using microbiology diagnostic tests of moderate or high complexity at the point - of - care in a delivery suite , 2012, Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology.

[32]  Gabriel J. Escobar,et al.  Estimating the Probability of Neonatal Early-Onset Infection on the Basis of Maternal Risk Factors , 2011, Pediatrics.

[33]  Lu Zhang,et al.  Acquired Antibiotic Resistance: Are We Born with It? , 2011, Applied and Environmental Microbiology.

[34]  T. Metsvaht,et al.  Risk factors associated with gut and nasopharyngeal colonization by common Gram-negative species and yeasts in neonatal intensive care units patients. , 2011, Early human development.

[35]  D. Cousins,et al.  Safer loading doses of medicines: summary of a safety report from the National Patient Safety Agency , 2011, BMJ : British Medical Journal.

[36]  S. Bryan,et al.  Cost‐effectiveness of rapid tests and other existing strategies for screening and management of early‐onset group B streptococcus during labour , 2010, BJOG : an international journal of obstetrics and gynaecology.

[37]  I. Petersen,et al.  Oral antibiotic prescribing during pregnancy in primary care: UK population-based study. , 2010, The Journal of antimicrobial chemotherapy.

[38]  P. Edelstein,et al.  Prevalence of Non-Penicillin-Susceptible Group B Streptococcus in Philadelphia and Specificity of Penicillin Resistance Screening Methods , 2010, Journal of Clinical Microbiology.

[39]  David J Torgerson,et al.  Bias in identifying and recruiting participants in cluster randomised trials: what can be done? , 2009, BMJ : British Medical Journal.

[40]  S Bryan,et al.  Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness. , 2009, Health technology assessment.

[41]  Ludovic Trinquart,et al.  Diagnostic accuracy of a rapid real-time polymerase chain reaction assay for universal intrapartum group B streptococcus screening. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[42]  S. Kenyon,et al.  Childhood outcomes after prescription of antibiotics to pregnant women with spontaneous preterm labour: 7-year follow-up of the ORACLE II trial , 2008, The Lancet.

[43]  C. Doré,et al.  A case definition for national and international neonatal bloodstream infection surveillance , 2008, Archives of Disease in Childhood Fetal and Neonatal Edition.

[44]  T. Colbourn,et al.  Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses. , 2007, Health technology assessment.

[45]  H. Simhan,et al.  Untreated asymptomatic group B streptococcal bacteriuria early in pregnancy and chorioamnionitis at delivery. , 2007, American journal of obstetrics and gynecology.

[46]  T. Colbourn,et al.  An overview of the natural history of early onset group B streptococcal disease in the UK. , 2007, Early human development.

[47]  Elisabeth Fenwick,et al.  A guide to cost-effectiveness acceptability curves. , 2005, The British journal of psychiatry : the journal of mental science.

[48]  M. Dinsmoor,et al.  Use of Intrapartum Antibiotics and the Incidence of Postnatal Maternal and Neonatal Yeast Infections , 2005, Obstetrics and gynecology.

[49]  A. Schuchat,et al.  Perinatal infections due to group B streptococci. , 2004, Obstetrics and gynecology.

[50]  J. Troendle,et al.  Prematurity is the major risk factor for late-onset group B streptococcus disease. , 2003, The Journal of infectious diseases.

[51]  P. Heath,et al.  Estimated early-onset group B streptococcal neonatal disease , 2003, The Lancet.

[52]  P. Cooper,et al.  Economic costs of post-natal depression in a high-risk British cohort , 2002, British Journal of Psychiatry.

[53]  S. Oddie,et al.  Risk factors for early onset neonatal group B streptococcal sepsis: case-control study , 2002, BMJ : British Medical Journal.

[54]  A. Ohlsson,et al.  Neonatal Escherichia coli infections: concerns regarding resistance to current therapy , 2000, Acta paediatrica.

[55]  S. Hollis,et al.  What is meant by intention to treat analysis? Survey of published randomised controlled trials , 1999, BMJ.

[56]  M. Kenward,et al.  Small sample inference for fixed effects from restricted maximum likelihood. , 1997, Biometrics.

[57]  V. Katz,et al.  Perinatal group B streptococcal infections across intact amniotic membranes. , 1988, The Journal of reproductive medicine.

[58]  H. Dillon,et al.  A prospective study of group B streptococcal bacteriuria in pregnancy. , 1981, American journal of obstetrics and gynecology.

[59]  F. Barrett,et al.  Transmission of group B streptococci among parturient women and their neonates. , 1973, The Journal of pediatrics.

[60]  E. S. Pearson,et al.  THE USE OF CONFIDENCE OR FIDUCIAL LIMITS ILLUSTRATED IN THE CASE OF THE BINOMIAL , 1934 .

[61]  S. Mehtar,et al.  Transmission of multidrug-resistant Gram-negative bacteria from colonized mothers to their infants: a systematic review and meta-analysis. , 2019, The Journal of hospital infection.

[62]  S. Schrag,et al.  Prevention of perinatal group B streptococcal disease--revised guidelines from CDC, 2010. , 2010, MMWR. Recommendations and reports : Morbidity and mortality weekly report. Recommendations and reports.

[63]  A. Adriaanse,et al.  Neonatal early onset group B streptococcal infection. A nine-year retrospective study in a tertiary care hospital , 1996, Journal of perinatal medicine.