Group B streptococcus infection during pregnancy and infancy: estimates of regional and global burden

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Study Justification:
– Group B streptococcus (GBS) infection during pregnancy can lead to severe outcomes in infants, including meningitis, sepsis, stillbirths, and neurodevelopmental impairment (NDI).
– There are data gaps in understanding the global burden of GBS infection, particularly regarding NDI.
– This study aims to address these gaps by analyzing multicountry datasets to estimate the burden of GBS infection during pregnancy and infancy.
Study Highlights:
– The study estimated that in 2020, approximately 19.7 million pregnant women globally were colonized with GBS.
– It estimated that there were 231,800 early-onset and 162,200 late-onset infant GBS cases, with varying mortality rates depending on access to skilled birth attendants.
– The study predicted that 37,100 children who recovered from GBS infection would develop moderate or severe NDI.
– Maternal GBS cases were estimated to be around 40,500, and GBS-related stillbirths were predicted to be around 46,200 in 2020.
– The study also found that GBS colonization was associated with a significant number of preterm births.
Recommendations for Lay Reader and Policy Maker:
– The study highlights the significant burden of GBS infection during pregnancy and infancy, including the risk of severe outcomes such as infant deaths and neurodevelopmental impairment.
– The findings emphasize the importance of investment in preventive strategies, such as maternal GBS immunization, to reduce the burden of GBS infection.
– Policy makers should consider the public health implications of the study’s findings and prioritize interventions to prevent GBS infection and its associated complications.
Key Role Players:
– Researchers and scientists involved in GBS infection research and prevention.
– Healthcare professionals, including obstetricians, pediatricians, and infectious disease specialists.
– Public health officials and policymakers responsible for maternal and child health programs.
– Non-governmental organizations (NGOs) working on maternal and child health issues.
– Funding agencies and foundations supporting research and interventions related to GBS infection.
Cost Items for Planning Recommendations:
– Research and surveillance activities to monitor GBS infection rates and outcomes.
– Development and implementation of maternal GBS immunization programs.
– Training and capacity-building for healthcare professionals on GBS prevention and management.
– Public awareness campaigns to educate pregnant women and their families about GBS infection and preventive measures.
– Strengthening healthcare systems to ensure access to skilled birth attendants and appropriate care for GBS-infected infants.
– Data collection and analysis to monitor the impact of interventions and evaluate their cost-effectiveness.
Please note that the cost items provided are general categories and not actual cost estimates. The actual cost of implementing the recommendations will depend on various factors, including the country context and specific intervention strategies.

The strength of evidence for this abstract is 8 out of 10.
The evidence in the abstract is strong, as it is based on a comprehensive analysis of aggregated data from multiple sources. The study used Bayesian hierarchical models to estimate the burden of Group B streptococcus (GBS) infection during pregnancy and infancy in 183 countries. The authors collated and meta-analyzed data from systematic reviews published in 2017, as well as new data on stillbirths and neurodevelopmental impairment. The study provides estimates for various outcomes, including maternal GBS colonization, infant GBS cases and deaths, NDI in children, maternal GBS cases, GBS stillbirths, and preterm births associated with GBS colonization. The authors also accounted for uncertainty in their estimates and conducted sensitivity analyses. To improve the evidence, future studies could focus on collecting more data on GBS-related outcomes, especially in low-income and middle-income countries, and include comparator groups to estimate the association between GBS and neurodevelopmental impairment.

Background: Group B streptococcus (GBS) colonisation during pregnancy can lead to invasive GBS disease (iGBS) in infants, including meningitis or sepsis, with a high mortality risk. Other outcomes include stillbirths, maternal infections, and prematurity. There are data gaps, notably regarding neurodevelopmental impairment (NDI), especially after iGBS sepsis, which have limited previous global estimates. In this study, we aimed to address this gap using newly available multicountry datasets. Methods: We collated and meta-analysed summary data, primarily identified in a series of systematic reviews published in 2017 but also from recent studies on NDI and stillbirths, using Bayesian hierarchical models, and estimated the burden for 183 countries in 2020 regarding: maternal GBS colonisation, iGBS cases and deaths in infants younger than 3 months, children surviving iGBS affected by NDI, and maternal iGBS cases. We analysed the proportion of stillbirths with GBS and applied this to the UN-estimated stillbirth risk per country. Excess preterm births associated with maternal GBS colonisation were calculated using meta-analysis and national preterm birth rates. Findings: Data from the seven systematic reviews, published in 2017, that informed the previous burden estimation (a total of 515 data points) were combined with new data (17 data points) from large multicountry studies on neurodevelopmental impairment (two studies) and stillbirths (one study). A posterior median of 19·7 million (95% posterior interval 17·9–21·9) pregnant women were estimated to have rectovaginal colonisation with GBS in 2020. 231 800 (114 100–455 000) early-onset and 162 200 (70 200–394 400) late-onset infant iGBS cases were estimated to have occurred. In an analysis assuming a higher case fatality rate in the absence of a skilled birth attendant, 91 900 (44 800–187 800) iGBS infant deaths were estimated; in an analysis without this assumption, 58 300 (26 500–125 800) infant deaths from iGBS were estimated. 37 100 children who recovered from iGBS (14 600–96 200) were predicted to develop moderate or severe NDI. 40 500 (21 500–66 200) maternal iGBS cases and 46 200 (20 300–111 300) GBS stillbirths were predicted in 2020. GBS colonisation was also estimated to be potentially associated with considerable numbers of preterm births. Interpretation: Our analysis provides a comprehensive assessment of the pregnancy-related GBS burden. The Bayesian approach enabled coherent propagation of uncertainty, which is considerable, notably regarding GBS-associated preterm births. Our findings on both the acute and long-term consequences of iGBS have public health implications for understanding the value of investment in maternal GBS immunisation and other preventive strategies. Funding: Bill & Melinda Gates Foundation.

We collated aggregated data for all outcomes (cases of maternal colonisation, iGBS cases in the first 3 months of life, deaths among infants younger than 3 months with iGBS, patients who recovered from iGBS with NDI, stillbirths caused by GBS, cases of maternal iGBS, and excess preterm births associated with maternal GBS colonisation). Most studies included were identified in a series of systematic reviews published in 2017,3, 7, 8, 9, 10, 14, 19, 20, 21 and we included new data on stillbirths and NDI. Note that the search strategy, selection criteria, data extraction, and assessment of study quality were described in the original publications of these systematic reviews. Bayesian hierarchical models22 were used to analyse the evidence. We estimated the absolute burden for 2020 on the basis of the country-specific numbers of births in the UN World Population Prospects 2019 for 183 countries included in the dataset based on population size (only countries with 90 000 or more inhabitants were listed). All relevant outcomes were studied as shown in figure 1 and panel 1, with predefined case definitions. Bayesian models allowed a coherent propagation of uncertainty in the estimation of the burden and accounted for the multilevel structure of the data (eg, for several outcomes, multiple studies were identified per region). Posterior medians and intervals (95% posterior intervals) were reported that account for the uncertainty in the parameter estimation; relevant sensitivity analyses were also reported. Parameters were estimated either at the country (eg, maternal colonisation), regional (eg, case fatality rate), or global (eg, risk of NDI after GBS meningitis) levels, depending on data availability (appendix pp 4–22). Details on the statistical models, including assumptions and prior probability distributions, are in the appendix (pp 4–22). Our estimation process followed the GATHER statement.18 Results are shown by Sustainable Development Goals regions. Overview of GBS colonisation in pregnancy and relevant outcomes During pregnancy, GBS can cause stillbirths, be associated with prematurity, and lead to maternal infection or, more rarely, death. Some newborn babies born to mothers who are GBS colonised develop invasive disease during the first week of life. Infants can also develop GBS disease between days 7 and 89. The fatality risk is high, and depends on adequate access to care. Of those children who survive the acute episode, some will be diagnosed with neurodevelopmental impairment. Neurodevelopmental impairment risks after GBS meningitis and GBS sepsis differ and were modelled separately. This figure was adapted from a study by Lawn and colleagues, with permission.3 GBS=group B streptococcus. GBS colonisation of the maternal genitourinary tract is associated with early-onset iGBS (EOGBS)24, 25 and quantification of its frequency is a key step in the estimation process. We included data from a systematic review,23 and developed a hierarchical model to regress country-level maternal GBS colonisation prevalence on country-level covariates.26 Using this approach, we estimated the colonisation prevalence in pregnant women for countries with and without GBS colonisation data, adjusting for study differences (appendix pp 4–5) in terms of the swab site and laboratory diagnostics, and accounting for parameter uncertainty. iGBS in infants might present as EOGBS (0–6 days) or LOGBS (7–89 days), and clinical syndromes include sepsis or meningitis (figure 1, panel 1). Given that routine surveillance data might underestimate EOGBS in most settings, as argued previously by Edmond and colleagues6 and Dagnew and colleagues,27 here we estimated the risk of EOGBS in neonates born to mothers who were GBS colonised. For modelling EOGBS risk, it was essential to consider intrapartum antibiotic prophylaxis use; hence we developed a model to regress study-level EOGBS risk in babies of mothers who were GBS colonised who received intrapartum antibiotic prophylaxis.2, 19 We used this regression in combination with national coverage data on intrapartum antibiotic prophylaxis, based primarily on a review with data for 92 countries,20 plus additional assumptions for those countries without data (appendix pp 6–7): we assumed 0% intrapartum antibiotic prophylaxis coverage in low-income countries and 80% coverage in high-income countries with no coverage data (appendix pp 6–7). In a secondary analysis, we used a Bayesian evidence synthesis model26 to combine data from studies directly assessing EOGBS incidence and studies estimating the risk of EOGBS among infants of mothers who were GBS colonised. Similar to EOGBS, cases of LOGBS are likely to be under-reported in surveillance systems. Hence, we used an approach similar to a previous analysis21 and estimated region-specific proportions of LOGBS compared with EOGBS, which provided a multiplication factor to apply to EOGBS estimates. Full details are in the appendix (pp 6–9). Since most EOGBS cases (68%) occur within 24 h of birth,21 we assumed a high case fatality rate of 90%, using similar assumptions to Seale and colleagues,7 for EOGBS cases without skilled birth attendance (a marker of low access to any health care, including antibiotic treatment). A dataset from UNICEF and WHO on country-level skilled birth attendance was used.28 For cases of patients with EOGBS with skilled birth attendance and all cases of LOGBS, we applied case fatality rates estimated by region on the basis of published literature (appendix pp 10–12). Assuming a fixed high mortality rate (of 90%) for cases of EOGBS without skilled birth attendance means that uncertainty in this parameter, which is key in the estimation of number of deaths, is not incorporated in the estimates. We also undertook a sensitivity analysis that considered the scenario that EOGBS without skilled birth attendance could have the same regional case fatality rate as EOGBS with skilled birth attendance. iGBS can lead to NDI in those who recover. In this analysis, we estimated the risk of moderate and severe impairments, which is more likely to be consistent across settings and study designs compared with milder NDI types; in the appendix (pp 15–16), we present the results of analyses that also considered mild NDIs. For meningitis, we used studies reviewed in 2017,14 novel data from a national cohort in Denmark (which included children with outcome data available at the age of 10 years),15 and reanalysis of data from a multicentre observational study29 performed in Argentina, India, Mozambique, Kenya, and South Africa including all meningitis cases, irrespective of age (4–17 participants in each centre, with a total of 38 participants); that study was performed as part of this research project. For GBS sepsis, we used data from the same study in Denmark (805 children with data at the age of 10 years) and four smaller studies (4–61 participants in each study, with a total of 109 participants), also reviewed in a systematic review by Kohli-Lynch and colleagues,14 for high-income countries; for low-income and middle-income countries, data from the aforementioned multicentre study were used (22–31 participants in each centre, with a total of 108 participants) in a separate meta-analysis. Note that data from the Argentinian site in the multicentre study were not included because the low proportion of identified patients who recovered from iGBS who were assessed might have been linked to selection bias. Definitions of NDI, including of moderate and severe presentations, are described in detail in these previous studies;14, 15, 30 both the Danish study and the multicentre study, done as part of this project, used multidomain definitions consistent with the Global Burden of Disease, Injuries, and Risk Factors Study.31 Since most of these studies did not include comparator groups, our analysis does not estimate the association between iGBS and NDI, but rather the risk of moderate and severe NDI in patients who recovered from iGBS. Hence, to estimate the number of NDI cases attributable to iGBS, we used the risk of moderate or severe NDI in children without a history of iGBS in the Danish study (2·1%) as a conservative estimate of the comparative risk. Although the Danish cohort is the largest to date, and included information into the second decade of life, it is probable that the counterfactual risk varies considerably within and between countries. Similar to the EOGBS case fatality rate in children with no access to skilled birth attendance, this counterfactual risk was assumed to be fixed; hence estimates do not incorporate uncertainty in this parameter. Another assumption is that the risk of NDI estimated in these analyses represents a lifelong risk, which is probably an underestimation, because most studies recruited children younger than 10 years. Data inputs included a literature review on the proportion of stillbirths with evidence of GBS infection, with six studies published after 2000, one of which also included data collected before that year.9 We updated the searches and identified no additional published studies, but were able to add unpublished data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network32 including seven study sites in Africa and Asia, corresponding to a total of 509 stillbirths. In the CHAMPS network, a panel of local experts evaluated all data available for stillbirths enrolled with a post-mortem investigation including clinical information and collection and testing of tissue and non-tissue specimens to establish whether GBS was involved in the causal chain leading to each stillbirth. We applied a hierarchical model to combine data within regions. For regions with no studies, we used the model to predict the proportion. Region-specific proportions of stillbirths caused by GBS were then applied to country-specific stillbirth risk from the Global Health Observatory data repository. Sensitivity analyses with different prior assumptions were included in the appendix (p 42). GBS also causes disease in pregnant women. The little research on this, all from high-income countries, was reviewed by Hall and colleagues.8 We used data reported in that review, together with those from a study in England,33 to estimate the risk of GBS-related morbidity during pregnancy or post partum (up to 42 days after delivery). Of note, the inclusion of the 2020 study in England was not the result of a systematic search but was suggested by the project’s Scientific Advisory Group. Since these studies, which primarily reported cases where GBS was cultured from blood or cerebrospinal fluid, or both, did not estimate risk given maternal GBS carriage, we applied our estimates directly to country-specific number of births. Using previously reported data,10 we estimated the association between maternal GBS colonisation and preterm births. To incorporate all available evidence,34 we performed a meta-analysis on case-control studies and used the posterior distribution of the coefficient as a prior distribution in a meta-analysis model of cohort and cross-sectional studies. The overall odds ratio was used, together with country-level frequencies of preterm births,35 to calculate the excess number of preterm births associated with maternal GBS colonisation. Two different approaches were used for this calculation, which also required estimated country-level prevalence of maternal GBS colonisation; in the appendix (pp 21–22), we present the results of the meta-analyses and describe these approaches. All analyses were done using the Hamiltonian Monte Carlo algorithm in PyStan (version 2.19), the interface for the Stan libraries in Python (version 3.7).36 Details on the models are presented in the appendix (pp 4–22, 43), including additional assumptions in our analyses and probable limitations. For the primary data collection in high-income, low-income, and middle-income countries, the overarching protocol for the observational study was granted ethics approval at the London School of Hygiene & Tropical Medicine (approval number 16246). Institutional review boards in each of the countries granted ethics approval (Argentina approval number protocol EGB-1; India approval numbers 11723 [Christian Medical College Vellore], 2019–7034 [Indian Council of Medical Research]; Kenya approval number SERU/CGMR-C/164/3882; Mozambique approval number 98/CNBS/2019; and South Africa approval number M190241), as well as the institutional review board of WHO (approval number ERC.0003169). The Danish electronic cohort study was approved by the Danish Data Protection Agency (record number 2015–57–0002). In the Netherlands, the study protocol (EPI-408) was submitted to the Centre for Clinical Expertise at the National Institute for Public Health and the Environment. The study protocol was exempted from further approval by an ethics research committee, according to Dutch law for medical research involving human patients. This study was reviewed by the Centers for Disease Control and Prevention and was conducted consistent with applicable federal law and Centers for Disease Control and Prevention policy. The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Based on the provided information, here are some potential innovations that could improve access to maternal health:

1. Development of a rapid and accurate diagnostic test for Group B streptococcus (GBS) colonisation during pregnancy: This would allow healthcare providers to quickly identify pregnant women who are at risk of transmitting GBS to their infants and take appropriate preventive measures.

2. Implementation of universal GBS screening during pregnancy: By making GBS screening a routine part of prenatal care, healthcare providers can identify pregnant women who are colonised with GBS and provide them with appropriate interventions, such as intrapartum antibiotic prophylaxis, to reduce the risk of transmission to their infants.

3. Expansion of access to intrapartum antibiotic prophylaxis: In areas where access to healthcare services is limited, efforts should be made to ensure that all pregnant women who are at risk of transmitting GBS receive intrapartum antibiotic prophylaxis. This may involve training healthcare providers in remote areas, improving transportation infrastructure, and increasing the availability of antibiotics.

4. Implementation of GBS vaccination programs: The development and widespread use of GBS vaccines could significantly reduce the burden of GBS-related infections in both mothers and infants. Vaccination programs should be targeted towards pregnant women, as well as potentially high-risk populations, such as those with certain medical conditions or socioeconomic factors.

5. Strengthening of healthcare systems: Improving access to maternal health services requires a well-functioning healthcare system. This includes ensuring an adequate number of skilled healthcare providers, improving infrastructure and equipment in healthcare facilities, and implementing effective referral systems to ensure that pregnant women receive timely and appropriate care.

6. Community education and awareness campaigns: Increasing awareness about the importance of maternal health and the risks associated with GBS infection can help empower pregnant women and their families to seek appropriate care. Community education programs can also provide information on preventive measures, such as proper hygiene practices and the importance of prenatal care.

It is important to note that the implementation of these innovations should be context-specific and take into account the local healthcare infrastructure, resources, and cultural factors.
AI Innovations Description
The recommendation to improve access to maternal health based on the provided description is to invest in maternal Group B streptococcus (GBS) immunization and other preventive strategies. The study highlights the burden of GBS infection during pregnancy, which can lead to severe outcomes such as stillbirths, maternal infections, prematurity, and infant deaths. It also emphasizes the long-term consequences, including neurodevelopmental impairment (NDI) in children who recover from GBS.

To address this issue and improve access to maternal health, the following actions can be taken:

1. Immunization: Investing in maternal GBS immunization can help prevent GBS colonization during pregnancy and reduce the risk of invasive GBS disease in infants. This preventive strategy can significantly reduce the burden of GBS-related complications.

2. Antibiotic prophylaxis: Ensuring access to intrapartum antibiotic prophylaxis for pregnant women who are GBS colonized can help prevent early-onset GBS disease in newborns. This intervention should be implemented in settings where it is feasible and appropriate.

3. Strengthening healthcare systems: Improving access to skilled birth attendants and quality healthcare services during childbirth is crucial for early detection and management of GBS infection. This includes ensuring access to appropriate antibiotic treatment for infected infants and mothers.

4. Awareness and education: Raising awareness among healthcare providers, pregnant women, and communities about the risks and consequences of GBS infection can lead to early detection, timely treatment, and improved outcomes. Education programs should focus on promoting preventive measures and the importance of seeking healthcare during pregnancy.

5. Research and surveillance: Continued research and surveillance on GBS infection, including its prevalence, risk factors, and outcomes, can provide valuable insights for developing effective interventions and monitoring their impact. This includes monitoring the effectiveness of immunization programs and evaluating the long-term neurodevelopmental outcomes in children affected by GBS.

By implementing these recommendations, access to maternal health can be improved, leading to a reduction in the burden of GBS-related complications and better health outcomes for mothers and infants.
AI Innovations Methodology
Based on the provided description, here are some potential recommendations to improve access to maternal health:

1. Strengthen Antenatal Care: Enhance antenatal care services to include routine screening and treatment for Group B streptococcus (GBS) colonization during pregnancy. This can help identify and manage GBS infections early, reducing the risk of adverse outcomes for both mothers and infants.

2. Improve Skilled Birth Attendance: Ensure access to skilled birth attendants during delivery, particularly in low-income settings where access to healthcare may be limited. Skilled birth attendants can provide appropriate care and interventions to prevent and manage GBS-related complications.

3. Increase Awareness and Education: Implement educational programs to raise awareness among pregnant women and healthcare providers about the risks and prevention of GBS infections. This can include information on the importance of prenatal care, hygiene practices, and the benefits of intrapartum antibiotic prophylaxis.

4. Strengthen Laboratory Capacity: Enhance laboratory capacity in healthcare facilities to enable accurate and timely diagnosis of GBS colonization and infections. This can facilitate targeted interventions and appropriate treatment for affected individuals.

To simulate the impact of these recommendations on improving access to maternal health, a methodology could involve the following steps:

1. Define Key Indicators: Identify key indicators related to access to maternal health, such as the proportion of pregnant women screened for GBS colonization, the proportion of births attended by skilled birth attendants, and the incidence of GBS-related complications.

2. Collect Baseline Data: Gather baseline data on the identified indicators from relevant sources, such as health records, surveys, and existing studies. This will provide a starting point for comparison and evaluation.

3. Define Scenarios: Develop different scenarios based on the recommendations, considering factors such as the level of implementation, coverage, and effectiveness of interventions. For example, scenarios could include different levels of antenatal care coverage or varying rates of skilled birth attendance.

4. Model Impact: Use statistical modeling techniques, such as Bayesian hierarchical models, to simulate the impact of the defined scenarios on the selected indicators. This involves analyzing the available data, estimating the burden of GBS-related complications, and projecting the potential changes under different scenarios.

5. Evaluate Results: Assess the simulated results to determine the potential impact of the recommendations on improving access to maternal health. Compare the outcomes of different scenarios to identify the most effective interventions and their potential benefits.

6. Refine and Iterate: Based on the evaluation, refine the recommendations and scenarios as necessary. Repeat the modeling process to further explore and optimize the potential impact of the interventions.

It is important to note that the methodology described above is a general framework and may require adaptation based on the specific context and data availability.

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