Timing of exposure assessment in studies on Group B streptococcus colonization and preterm birth.

BACKGROUND: Maternal colonization by the bacterium Group B streptococcus (GBS) increases risk of preterm birth, a condition that has an important impact on the health of children. However, research studies that quantify the effect of GBS colonization on preterm birth have reported variable estimates of the effect measure. METHODS: We performed a simulated cohort study of pregnant women to assess how timing of exposure (GBS colonization) assessment might influence results of studies that address this question. We used published data on longitudinal maternal GBS colonization and on the distribution of preterm births by gestational age to inform parameters used in the simulations. RESULTS: Assuming that the probability of preterm birth is higher during weeks when pregnant women are colonized by GBS, our results suggest that studies that assess exposure status early during pregnancy are more likely to estimate an association between GBS colonization and preterm birth that is closer to the null, compared with studies that assess exposure either at birth or during gestational weeks matched to preterm births. In sensitivity analyses assuming different colonization acquisition rates and diagnostic sensitivities, we observed similar results. CONCLUSIONS: Accurate quantification of the effect of maternal GBS colonization on the risk of preterm birth is necessary to understand the full health burden linked to this bacterium. In this study, we investigated one possible explanation, related to the timing of exposure assessment, for the variable findings of previous observational studies. Our findings will inform future research on this question.

Long-term healthcare utilisation, costs and quality of life after invasive group B Streptococcus disease: a cohort study in five low-income and middle-income countries.

INTRODUCTION: There are no published data on the long-term impact of invasive group B Streptococcus disease (iGBS) on economic costs or health-related quality of life (HRQoL) in low-income and middle-income countries. We assessed the impact of iGBS on healthcare utilisation, costs and HRQoL in Argentina, India, Kenya, Mozambique and South Africa. METHODS: Inpatient and outpatient visits, out-of-pocket (OOP) healthcare payments in the 12 months before study enrolment, and health-state utility of children and caregivers (using the EuroQol 5-Dimensions-3-Level) were collected from iGBS survivors and an unexposed cohort matched on site, age at recruitment and sex. We used logistic or Poisson regression for analysing healthcare utilisation and zero-inflated gamma regression models for family and health system costs. For HRQoL, we used a zero-inflated beta model of disutility pooled data. RESULTS: 161 iGBS-exposed and 439 unexposed children and young adults (age 1-20) were included in the analysis. Compared with unexposed participants, iGBS was associated with increased odds of any healthcare utilisation in India (adjusted OR 11.2, 95% CI 2.9 to 43.1) and Mozambique (6.8, 95% CI 2.2 to 21.1) and more frequent healthcare visits (adjusted incidence rate ratio (IRR) for India 1.7 (95% CI 1.4 to 2.2) and for Mozambique 6.0 (95% CI 3.2 to 11.2)). iGBS was also associated with more frequent days in inpatient care in India (adjusted IRR 4.0 (95% CI 2.3 to 6.8) and Kenya 6.4 (95% CI 2.9 to 14.3)). OOP payments were higher in the iGBS cohort in India (adjusted mean: Int$682.22 (95% CI Int$364.28 to Int$1000.16) vs Int$133.95 (95% CI Int$72.83 to Int$195.06)) and Argentina (Int$244.86 (95% CI Int$47.38 to Int$442.33) vs Int$52.38 (95% CI Int$-1.39 to Int$106.1)). For all remaining sites, differences were in the same direction but not statistically significant for almost all outcomes. Health-state disutility was higher in iGBS survivors (0.08, 0.04-0.13 vs 0.06, 0.02-0.10). CONCLUSION: The iGBS health and economic burden may persist for years after acute disease. Larger studies are needed for more robust estimates to inform the cost-effectiveness of iGBS prevention.

Development and early testing of a simple, low cost, fast sensor for maternal and neonatal group B Streptococcus.

Streptococcus agalactiae, (Group B Streptococcus (GBS)), is a common colonizer of the female vagina. In women giving birth it can be transmitted to the baby and cause serious illness and even death to the child. We have developed a biosensor comprising of phospholipids and fatty acids vesicles encapsulating high concentration, self-quenched carboxyfluorescein, which is released by the lysis of the vesicle by virulence factors expressed by GBS, becoming diluted and fluorescent. The microbial specificity of the sensor was tested against a number of GBS strains and other microbes including Candida albicans, Enterococcus faecalis and Staphylococcus epidermidis and a statistically significant response to GBS measured over these other microbes. To test the invivo efficacy of the biosensor, a pilot study using donated lower vaginal swabs from non-pregnant women was conducted, where 58 female adults were recruited. Participants donated two swabs, one which was used for the vesicle test and one for the 'gold standard', enriched culture media (ECM) test. An overall GBS carriage rate of 17.2% was measured using the ECM test. The vesicle biosensor test took 45 min to obtain a result, and showed a sensitivity of 83.3%, specificity of 85.7% and accuracy of 85.3%. The test accuracy is in line with current novel GBS identification tests, with the advantage of being rapid, easy to use, low-cost and able to be conducted by bedside during start of labour.

Using Azadirachta indica protein hydrolysate as a plant protein in Nile tilapia (Oreochromis niloticus) diet: Effects on the growth, economic efficiency, antioxidant-immune response and resistance to Streptococcus agalactiae.

A feeding trial for 90 days was conducted on Nile tilapia (Oreochromis niloticus) (average weight: 25.50 ± 0.05 g) to evaluate the effect of dietary inclusion of Azadirachta indica seed protein hydrolysate (AIPH). The evaluation included the impact on the growth metrics, economic efficiency, antioxidant potential, hemato-biochemical indices, immune response, and histological architectures. A total of 250 fish were randomly distributed in five treatments (n = 50) and received diets included with five levels of AIPH (%): 0 (control diet, AIPH0), 2 (AIPH2), 4 (AIPH4), 6 (AIPH6) or 8 (AIPH8), where AIPH partially replace fish meal by 0, 8.7%, 17.4%, 26.1%, and 34.8%, respectively. After the feeding trial, a pathogenic bacterium (Streptococcus agalactiae, 1.5 × 108 CFU/mL) was intraperitoneally injected into the fish and the survival rate was recorded. The results elucidated that AIPH-included diets significantly (p < 0.05) enhanced the growth indices (final body weight, total feed intake, total body weight gain, and specific growth rate) and intestinal morpho-metrics (villous width, length, muscular coat thickness, and goblet cells count) in comparison to the control diet, with the AIPH8 diet recording the highest values. Dietary AIPH inclusion significantly improved (p < 0.05) the economic efficacy indicated by reduced feed cost/kg gain and increased performance index. The fish fed on the AIPH diets had noticeably significantly higher (p < 0.05) protein profile variables (total proteins and globulin) and antioxidant capabilities (superoxide dismutase and total antioxidant capacity) than the AIPH0 group. The dietary inclusion of AIPH significantly (p < 0.05) boosted the haematological parameters (haemoglobin, packed cell volume %, and counts of red blood cells and white blood cells) and immune indices (serum bactericidal activity %, antiprotease activity, and immunoglobulin M level) in a concentration-dependent manner. The blood glucose and malondialdehyde levels were significantly (p < 0.05) lowered by dietary AIPH (2%-8%). The albumin level and hepatorenal functioning parameters (aspartate aminotransferase, alanine aminotransferase, and creatinine) were not significantly (p > 0.05) altered by AIPH diets. Additionally, AIPH diets did not adversely alter the histology of the hepatic, renal or splenic tissues with moderately activated melano-macrophage centres. The mortality rate among S. agalactiae-infected fish declined as dietary AIPH levels rose, where the highest survival rate (86.67%) was found in the AIPH8 group (p < 0.05). Based on the broken line regression model, our study suggests using dietary AIPH at the optimal level of 6%. Overall, dietary AIPH inclusion enhanced the growth rate, economic efficiency, health status, and resistance of Nile tilapia to the S. agalactiae challenge. These beneficial impacts can help the aquaculture sector to be more sustainable.

Maternal immunisation against Group B Streptococcus: A global analysis of health impact and cost-effectiveness.

BACKGROUND: Group B Streptococcus (GBS) can cause invasive disease (iGBS) in young infants, typically presenting as sepsis or meningitis, and is also associated with stillbirth and preterm birth. GBS vaccines are under development, but their potential health impact and cost-effectiveness have not been assessed globally. METHODS AND FINDINGS: We assessed the health impact and value (using net monetary benefit (NMB), which measures both health and economic effects of vaccination into monetary units) of GBS maternal vaccination in an annual cohort of 140 million pregnant women across 183 countries in 2020. Our analysis uses a decision tree model, incorporating risks of GBS-related health outcomes from an existing Bayesian disease burden model. We extrapolated country-specific GBS-related healthcare costs using data from a previous systematic review and calculated quality-adjusted life years (QALYs) lost due to infant mortality and long-term disability. We assumed 80% vaccine efficacy against iGBS and stillbirth, following the WHO Preferred Product Characteristics, and coverage based on the proportion of pregnant women receiving at least 4 antenatal visits. One dose was assumed to cost $50 in high-income countries, $15 in upper-middle income countries, and $3.50 in low-/lower-middle-income countries. We estimated NMB using alternative normative assumptions that may be adopted by policymakers. Vaccinating pregnant women could avert 127,000 (95% uncertainty range 63,300 to 248,000) early-onset and 87,300 (38,100 to 209,000) late-onset infant iGBS cases, 31,100 deaths (14,400 to 66,400), 17,900 (6,380 to 49,900) cases of moderate and severe neurodevelopmental impairment, and 23,000 (10,000 to 56,400) stillbirths. A vaccine effective against GBS-associated prematurity might also avert 185,000 (13,500 to 407,000) preterm births. Globally, a 1-dose vaccine programme could cost $1.7 billion but save $385 million in healthcare costs. Estimated global NMB ranged from $1.1 billion ($-0.2 to 3.8 billion) under the least favourable normative assumptions to $17 billion ($9.1 to 31 billion) under the most favourable normative assumptions. The main limitation of our analysis was the scarcity of data to inform some of the model parameters such as those governing health-related quality of life and long-term costs from disability, and how these parameters may vary across country contexts. CONCLUSIONS: In this study, we found that maternal GBS vaccination could have a large impact on infant morbidity and mortality. Globally, a GBS maternal vaccine at reasonable prices is likely to be a cost-effective intervention.

Economic appraisal of using genetics to control Streptococcus agalactiae in Nile tilapia under cage and pond farming system in Malaysia.

Disease outbreaks have been seen as the major threat to sustainable aquaculture worldwide. Injectable vaccines have been one of the few strategies available to control the diseases, however, the adoption of this technology globally is limited. Genetic selection for disease resistance has been proposed as the alternative strategy in livestock and aquaculture. Economic analysis for such strategies is lacking and this study assesses the economic worth of using tilapia fingerlings resistant to Streptococcosis in both cage and pond production systems. The paper also assesses the profitability of paying the higher price for such fingerlings. Partial-budgeting was used to develop a stochastic simulation model that considers the benefits and costs associated with the adoption of tilapia fingerlings resistant to Streptococcosis at the farm level, in one production cycle. In both ponds and cage production systems, the use of genetically selected Streptococcus resistant tilapia fingerlings was found to be profitable where Streptococcus infection is prevalent. In the cages and ponds where Streptococcus related mortality was ≥ 10%, the Nile tilapia aquaculture was found to be profitable even if the amount paid for genetically selected Streptococcus resistant tilapia fingerlings was 100% higher than the amount paid for standard fingerlings.

Reduction of intrapartum antibiotic prophylaxis by combining risk factor assessment with a rapid bedside intrapartum polymerase chain reaction testing for group B streptococci.

OBJECTIVE: To investigate the impact of administering Intrapartum Antibiotic Prophylaxis (IAP) to laboring women with one or more risk factors for Early Onset Group B Streptococcal neonatal infection (EOGBS) based on the result of a rapid bedside test for Group B Streptococci (GBS). STUDY DESIGN: Quality assessment study. METHODS: Three-hundred-sixty-six laboring women admitted to our maternity ward, with one or more risk factors for EOGBS, were prospectively included. Rectovaginal swab-samples were examined bedside by the GenomEra® GBS Polymerase Chain Reaction (PCR) assay upon admission. Time from administration of IAP to delivery was registered. According to national guidelines, one-hundred-two women mandatorily received IAP independent of the PCR test result fulfilling one of the following three risk factors: prior infant with EOGBS, preterm labor before 35 gestational week, temperature ≥ 38 °C during labor. Women with GBS bacteriuria during current pregnancy, rupture of membranes ≥ 18 h IAP, and preterm labor between 35 and 37 gestational week, received IAP solely if the PCR test was positive. Predictive values were calculated for each risk factor. RESULTS: Previous GBS bacteriuria was strongly associated (PPV = 71%) with a positive GBS PCR test, whilst the corresponding positive percent of ROM > 18 h and of GA 35-37 was only PPV = 16% and 22%, respectively. Seventy-four women, 74/251 (31%), received IAP because they were GBS PCR positive. IAP was thus reduced by about two-thirds compared to the risk-based strategy of offering IAP to all women with one or more risk factors for EOGBS. Two women, 2/254 (0.8%), received inferior care, as they did not receive IAP within the recommended 4 h prior to delivery due to the extra time spend on the test procedure. CONCLUSION: Bedside intrapartum PCR testing of women with risk factors for EOGBS effectively diminishes use of IAP during labor compared to the present risk factor-based strategy alone. In this project, the extra time spend on the PCR test procedure did not lead to noticeable delay in IAP.

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.

WHAT IS THE PROBLEM?: Group B Streptococcus is a common bacterium found in the vagina and intestines of approximately one in four women. Group B Streptococcus may be passed to the baby around birth and cause severe infection. In the UK, women are offered antibiotics in labour to protect their baby from group B Streptococcus infection when specific risk factors are present. Most women with risk factors do not carry group B Streptococcus and their babies are unnecessarily exposed to antibiotics. Most women carrying group B Streptococcus do not have risk factors and so will not be offered antibiotics to protect their babies. WHAT DID WE PLAN TO DO?: We planned to find out if, for women with risk factors, a 'rapid test' in labour resulted in fewer women receiving antibiotics compared with 'usual care'. We also wanted to establish if the test correctly identified if mothers were carrying group B Streptococcus, helped reduce infections in babies and represented value for money. WHAT DID WE FIND?: We involved 1627 women (1700 babies) from 20 hospitals randomly allocated to rapid test or usual care. Using the 'rapid test' did not reduce antibiotics provided to mothers (41% in rapid test units and 36% in usual-care units). The test correctly identified 86% of women carrying group B Streptococcus, 89% of those who did not and failed to provide a result in 14% of women. A rapid test policy resulted in 13% fewer babies receiving antibiotics. The rapid test generated no cost savings when only the mothers' care was considered, but there was potential for reduced costs when including the newborns' hospital stay. WHAT DOES THIS MEAN?: The rapid test is accurate; however, using it for women with risk factors for their baby developing group B Streptococcus infection does not reduce antibiotic usage in mothers, although it does in babies. Value for money is uncertain and depends on what costs are included.

Immediate birth for women between 34 and 37 weeks of gestation with prolonged preterm prelabour rupture of membranes and detection of vaginal or urine group B streptococcus: an economic evaluation.

OBJECTIVE: What are the costs, benefits and harms of immediate birth compared with expectant management in women with prolonged preterm prelabour rupture of membranes (PPROM) at 34+0 -36+6  weeks of gestation and detection of vaginal or urine group B streptococcus (GBS)? DESIGN: Mathematical decision model comprising three independent decision trees. SETTING: UK National Health Service (NHS) and personal social services perspective. POPULATION: Women testing positive for GBS with PPROM at 34+0 -36+6  weeks of gestation. METHODS: The model estimates lifetime costs and quality-adjusted life years (QALYs) using evidence from randomised trials, UK NHS data sources and further observational studies. Simulated events include neonatal infections, morbidity associated with preterm birth and consequences of caesarean birth. Deterministic and probabilistic sensitivity analyses (PSAs) were performed. MAIN OUTCOME MEASURES: QALYs, costs and incremental cost-effectiveness ratio (ICER). RESULTS: In this population, immediate birth dominates expectant management: it is more effective (average lifetime QALYs, 24.705 versus 24.371) and it is cheaper (average lifetime costs, £14,372 versus £19,311). In one-way sensitivity analysis, results are robust to all but the odds ratio estimating the relative effect on incidence of infections. Threshold analysis shows that the odds of infection only need to be >1.5% with expectant management for the benefit of avoiding infections to outweigh the disadvantages of immediate birth. In PSA, immediate birth is the preferred option in >80% of simulations. CONCLUSIONS: Neonatal GBS infections are expensive to treat and may result in substantial adverse health consequences. Therefore, immediate birth, which is associated with a reduced risk of neonatal infection compared with expectant management, is expected to generate better health outcomes and decreased lifetime costs. TWEETABLE ABSTRACT: For women with preterm prelabour rupture of membranes and group B streptococcus in vaginal or urine samples, immediate birth is associated with improved health in their babies and reduced costs, compared with expectant management.

A Financial and Global Demand Analysis to Inform Decisions for Funding and Clinical Development of Group B Streptococcus Vaccines for Pregnant Women.

BACKGROUND: Despite group B Streptococcus (GBS) being a leading cause of maternal and infant morbidity and mortality, no vaccine is currently available. To inform vaccine developers, countries, and funders, we analyzed the key factors likely to influence the demand for a GBS vaccine and the long-term financial sustainability for a vaccine developer. METHODS: Using population-based forecasting, we estimated the demand for a GBS vaccine; using a discounted cash flow model we estimated the financial viability for a vaccine developer. RESULTS: Demand for this vaccine can be significant if countries adopt policy recommendations for use, in particular, the largest ones, most of which have a burden that justifies use of the vaccine, and if financing for the vaccine is made available either by countries or by funding mechanisms such as Gavi, the Vaccine Alliance. CONCLUSIONS: This analysis suggests the potential for financial and commercial viability for a vaccine developer pursuing the commercialization of a GBS vaccine. Risks exists in relation to the clinical trial design and costs, the level of competition, countries' ability to pay, the administration schedule, and the availability of policies that encourage use of the vaccine. To reduce those risks and ensure equitable access to a GBS vaccine, the role of donors or financers can prove very important, as can a coordinated operational research agenda that aims at clarifying those areas of uncertainty.

Avaliação de colonização por Streptococcus agalactiae em gestantes atendidas em um laboratório de análises clínicas da Serra Gaúcha / Rio Grande do Sul / Assessment of Streptococcus agalactiae colonization in pregnant women attending a clinical laboratory in southern Brazil

Introdução: O Streptococcus agalactiae é uma bactéria Gram-positiva, cocoide, disposta em cadeias ou aos pares e coloniza o trato gastrointestinal e geniturinário, podendo se tornar um agente causador de patologias. Recém-nascidos são os mais afetados pela colonização do S. agalactiae, com manifestações clínicas de pneumonia, meningite a sepse, porém gestantes também são suscetíveis a infecção por esta bactéria.Métodos: A coleta de dados foi realizada através do sistema informatizado do laboratório coparticipante. Foi selecionado o período de 01 de janeiro de 2016 a 31 de dezembro de 2020, exame Pesquisa de Streptococcus B (PEB) com coleta por swab em região vaginal e anorretal e idade das gestantes. Após obtenção dos dados, os resultados foram tabulados em planilhas do Excel 2016 para posterior análise.Resultados: O percentual de positividade de colonização por S. agalactiae entre as gestantes foi de 18,6% de um total de 1385 gestantes. O ano de 2016 apresentou os menores índices de colonização com 14,5% (32/220) e o ano de 2020, os maiores, com 26,3% (84/319). A idade das participantes variou de 13 a 54 anos, com média de 29,08 anos e mediana de 29 anos.Conclusão: O presente estudo pôde evidenciar um alto índice de colonização por S. agalactiae entre as gestantes atendidas pelo laboratório coparticipante durante os anos pesquisados. Como também demonstrar a importância da pesquisa de colonização por S. agalactiae em gestantes durante o pré-natal, pois assim se torna possível a correta profilaxia para evitar futuras complicações nos recém-nascidos como também nas mães.

Introduction:Streptococcus agalactiae is a gram-positive bacterium, coccoid bacterium, arranged in chains or pairs that colonizes the gastrointestinal and genitourinary tracts, and may become a causative agent of diseases. Newborns are the most affected by S. agalactiae colonization, with clinical manifestations of pneumonia, meningitis and sepsis, but pregnant women are also susceptible to infection caused by this bacterium.Methods: Data were collected using the computerized system of the co-participating laboratory. The following variables were select: period from January 1, 2016 to December 31, 2020, Streptococcus B screening with collection of vaginal an anorectal swabs and age of the pregnant women. After data were obtained, the results were tabulated in Excel 2016 spreadsheets for further analysis.Results: The percentage of positive S. agalactiae colonizacion in pregnant women was 18.6% of a total of 1,385 pregnant women. The year 2016 had the lowest colonization rate with 14.5% (32/220), and the year 2020 had the highest rate with 26.3% (84/319). The age of the participants ranged from 13 to 54 years, with a mean of 29.08 years and a median of 29 years.Conclusion: The present study showed a high rate of S. agalactiae colonization among pregnant women attending the co-participating laboratory during the study period. It also demonstrated the importance of S. agalactiae colonization screening in pregnant women during prenatal care, as this allows to correct prophylaxis to avoid future complications in both newborns and mothers.

Burden of invasive group B Streptococcus disease in non-pregnant adults: A systematic review and meta-analysis.

BACKGROUND: Streptococcus agalactiae or group B Streptococcus (GBS) has emerged as an important cause of invasive disease in adults, particularly among the elderly and those with underlying comorbidities. Traditionally, it was recognised as an opportunistic pathogen colonising and causing disease in pregnant women, neonates, and young infants. Reasons for the upsurge of invasive GBS (iGBS) among the elderly remain unclear, although it has been related to risk factors such as underlying chronic diseases, immunosenescence, impaired inflammatory response, and spread of virulent clones. Antibiotics are successfully as treatment or prophylaxis against iGBS. Several candidate vaccines against iGBS are under development. OBJECTIVES: To conduct a systematic review of the current literature on invasive GBS in order to determine disease incidence and case fatality ratio (CFR) among non-pregnant adults. Additionally, information on risk factors, clinical presentation, serotype distribution, and antimicrobial resistance was also retrieved. METHODS: Between January and June 2020, electronic searches were conducted in relevant databases: MEDLINE, EMBASE, Global Health, and SCOPUS. Studies were included in the systematic review if they met the inclusion/exclusion criteria. The authors assessed the selected studies for relevance, risk of bias, outcome measures, and heterogeneity. Meta-analyses on incidence and CFR were conducted after evaluating the quality of methods for assessment of exposure and outcomes. RESULTS: Pooled estimates of iGBS incidence in non-pregnant adults 15 years and older were 2.86 cases per 100.000 population (95% CI, 1.68-4.34). Incidence rates in older adults were substantially higher, 9.13 (95%CI, 3.53-17.22) and 19.40 (95%CI, 16.26-22.81) per 100.000 population ≥50 and ≥ 65 years old, respectively. Incidence rates ranged from 0.40 (95% CI, 0.30-0.60) in Africa to 5.90 cases per 100.000 population (95% CI, 4.30-7.70) in North America. The overall CFR was and 9.98% (95% CI, 8.47-11.58). CFR was highest in Africa at 22.09% (95% CI, 12.31-33.57). Serotype V was the most prevalent serotype globally and in North America accounting for 43.48% (n = 12926) and 46,72% (n = 12184) of cases, respectively. Serotype Ia was the second and serotype III was more prevalent in Europe (25.0%) and Asia (29.5%). Comorbidities were frequent among non-pregnant adult iGBS cases. Antimicrobial resistance against different antibiotics (i.e., penicillin, erythromycin) is increasing over time. CONCLUSIONS: This systematic review revealed that iGBS in non-pregnant adults has risen in the last few years and has become a serious public health threat especially in older adults with underlying conditions. Given the current serotype distribution, vaccines including serotypes predominant among non-pregnant adults (i.e., serotypes V, Ia, II, and III) in their formulation are needed to provide breadth of protection. Continued surveillance monitoring potential changes in serotype distribution and antimicrobial resistance patterns are warranted to inform public health interventions.

Estimation of country-level incidence of early-onset invasive Group B Streptococcus disease in infants using Bayesian methods.

Neonatal invasive disease caused by Group B Streptococcus (GBS) is responsible for much acute mortality and long-term morbidity. To guide development of better prevention strategies, including maternal vaccines that protect neonates against GBS, it is necessary to estimate the burden of this condition globally and in different regions. Here, we present a Bayesian model that estimates country-specific invasive GBS (iGBS) disease incidence in children aged 0 to 6 days. The model combines different types of epidemiological data, each of which has its own limitations: GBS colonization prevalence in pregnant women, risk of iGBS disease in children born to GBS-colonized mothers and direct estimates of iGBS disease incidence where available. In our analysis, we present country-specific maternal GBS colonization prevalence after adjustment for GBS detection assay used in epidemiological studies. We then integrate these results with other epidemiological data and estimate country-level incidence of iGBS disease including in countries with no studies that directly estimate incidence. We are able to simultaneously estimate two key epidemiological quantities: the country-specific incidence of early-onset iGBS disease, and the risk of iGBS disease in babies born to GBS-colonized women. Overall, we believe our method will contribute to a more comprehensive quantification of the global burden of this disease, inform cost-effectiveness assessments of potential maternal GBS vaccines and identify key areas where data are necessary.

Cost-effectiveness of maternal immunization against neonatal invasive Group B Streptococcus in the Netherlands.

BACKGROUND: Neonatal invasive Group B Streptococcus (GBS) infection causes considerable disease burden in the Netherlands. Intrapartum antibiotic prophylaxis (IAP) prevents early-onset disease (EOD), but has no effect on late-onset disease (LOD). A potential maternal GBS vaccine could prevent both EOD and LOD by conferring immunity in neonates. OBJECTIVE: Explore under which circumstances maternal vaccination against GBS would be cost-effective as an addition to, or replacement for the current risk factor-based IAP prevention strategy in the Netherlands. METHODS: We assessed the maximum cost-effective price per dose of a trivalent (serotypes Ia, Ib, and III) and hexavalent (additional serotypes II, IV, and V) GBS vaccine in addition to, or as a replacement for IAP. To project the prevented costs and disease burden, a decision tree model was developed to reflect neonatal GBS disease and long-term health outcomes among a cohort based on 169,836 live births in the Netherlands in 2017. RESULTS: Under base-case conditions, maternal immunization with a trivalent vaccine would gain 186 QALYs and prevent more than €3.1 million in health care costs when implemented in addition to IAP. Immunization implemented as a replacement for IAP would gain 88 QALYs compared to the current prevention strategy, prevent €1.5 million in health care costs, and avoid potentially ~ 30,000 IAP administrations. The base-case results correspond to a maximum price of €58 per dose (vaccine + administration costs; using a threshold of €20,000/QALY). Expanding the serotype coverage to a hexavalent vaccine would only have a limited additional impact on the cost-effectiveness in the Netherlands. CONCLUSIONS: A maternal GBS vaccine could be cost-effective when implemented in addition to the current risk factor-based IAP prevention strategy in the Netherlands. Discontinuation of IAP would save costs and prevent antibiotic use, however, is projected to lead to a lower health gain compared to vaccination in addition to IAP.

Mortality, neurodevelopmental impairments, and economic outcomes after invasive group B streptococcal disease in early infancy in Denmark and the Netherlands: a national matched cohort study.

BACKGROUND: Group B Streptococcus (GBS) disease is a leading cause of neonatal death, but its long-term effects have not been studied after early childhood. The aim of this study was to assess long-term mortality, neurodevelopmental impairments (NDIs), and economic outcomes after infant invasive GBS (iGBS) disease up to adolescence in Denmark and the Netherlands. METHODS: For this cohort study, children with iGBS disease were identified in Denmark and the Netherlands using national medical and administrative databases and culture results that confirmed their diagnoses. Exposed children were defined as having a history of iGBS disease (sepsis, meningitis, or pneumonia) by the age of 89 days. For each exposed child, ten unexposed children were randomly selected and matched by sex, year and month of birth, and gestational age. Mortality data were analysed with the use of Cox proportional hazards models. NDI data up to adolescence were captured from discharge diagnoses in the National Patient Registry (Denmark) and special educational support records (the Netherlands). Health care use and household income were also compared between the exposed and unexposed cohorts. FINDINGS: 2258 children-1561 in Denmark (born from Jan 1, 1997 to Dec 31, 2017) and 697 in the Netherlands (born from Jan 1, 2000 to Dec 31, 2017)-were identified to have iGBS disease and followed up for a median of 14 years (IQR 7-18) in Denmark and 9 years (6-11) in the Netherlands. 366 children had meningitis, 1763 had sepsis, and 129 had pneumonia (in Denmark only). These children were matched with 22 462 children with no history of iGBS disease. iGBS meningitis was associated with an increased mortality at age 5 years (adjusted hazard ratio 4·08 [95% CI 1·78-9·35] for Denmark and 6·73 [3·76-12·06] for the Netherlands). Any iGBS disease was associated with an increased risk of NDI at 10 years of age, both in Denmark (risk ratio 1·77 [95% CI 1·44-2·18]) and the Netherlands (2·28 [1·64-3·17]). A history of iGBS disease was associated with more frequent outpatient clinic visits (incidence rate ratio 1·93 [95% CI 1·79-2·09], p<0·0001) and hospital admissions (1·33 [1·27-1·38], p<0·0001) in children 5 years or younger. No differences in household income were observed between the exposed and unexposed cohorts. INTERPRETATION: iGBS disease, especially meningitis, was associated with increased mortality and a higher risk of NDIs in later childhood. This previously unquantified burden underlines the case for a maternal GBS vaccine, and the need to track and provide care for affected survivors of iGBS disease. FUNDING: The Bill & Melinda Gates Foundation. TRANSLATIONS: For the Dutch and Danish translations of the abstract see Supplementary Materials section.

[Decrease in Group B Streptococcal Infections in Neonates: Analysis of Health Insurance Data 2005 to 2017]. / Rückgang von Infektionen durch Streptokokken der Gruppe B bei Neugeborenen: Analyse von Krankenversicherungsdaten 2005 bis 2017.

BACKGROUND: In the German guidelines for prophylaxis of group B streptococcal (GBS) early onset sepsis in neonates (EOS), GBS screening of all pregnant women has been recommended, but is not yet included in the Maternity Directives. Aim of the study was to identify temporal trends in incidence of EOS and their association to GBS Screening. METHODS: The analysis based on health insurance data of the statutory health insurance provider Barmer from 2005 to 2017 of 313,385 mother-child pairs. Annual frequency of GBS infections in newborns was determined by ICD-10 P36.0. The frequency of maternal GBS colonization was indicated by ICD-10 B95.1, which was used as surrogate for GBS screening. Temporal trends of the risk of EOS in neonates were assessed in logistic regression models. Pearson's correlation coefficient of EOS incidence and the surrogate marker for maternal GBS colonization was calculated. RESULTS: The risk of EOS in neonates caused by GBS has decreased annually by 9.3%, resulting in an overall decrease in the observation period of 72.0%. There was no statistical significant change in the risk for LOS (Late Onset Sepsis). The decrease of EOS could not be explained by temporal changes in Caesarian section, risk factors or preterm delivery. The 3.5 fold increase in the proportion of mothers with documented positive GBS colonization in the same period correlated inversely with the incidence of EOS (r=- 0.75; p=0.002). CONCLUSION: The decrease of EOS in neonates caused by GBS in Germany and the unchanged risk of LOS in neonates may be explained by the increasing application of the GBS Screening in pregnant women.