Prospective multicenter evaluation of adherence to the Dutch guideline for children aged 0-16 years with fever without a source-febrile illness in children (FINCH) study.

Evaluation of guidelines in actual practice is a crucial step in guideline improvement. A retrospective evaluation of the Dutch guideline for children with fever without an apparent source (FWS) showed 50% adherence in young infants. We prospectively evaluated adherence to the Dutch guideline and its impact on management in current practice. Prospective observational multicenter cross-sectional study, including children 3 days to 16 years old presented for FWS at one of seven emergency departments in participating secondary and tertiary care hospitals in the Netherlands. Adherence to the Dutch FWS guideline, adapted from the National Institute for Health and Care Excellence (NICE) guideline, was evaluated, and patterns in non-adherence and the impact of non-adherence on clinical outcomes and resource use were explored. Adherence to the guideline was 192/370 (52%). Adherence was lowest in patients categorized as high risk for severe infection (72/187, 39%), compared to the low-risk group (64/73, 88%). Differences in adherence were significant between risk categories (P < 0.001) but not between age categories. In case of non-adherence, less urinalysis, fewer bacterial cultures (blood, urine, and cerebral spinal fluid), and less empirical antibiotic treatment were performed (P < 0.050). Clinical outcomes were not significantly different between the non-adherence and the adherence group, particularly regarding missed severe infections. CONCLUSIONS: We found a high non-adherence rate of 48%, which did not lead to unfavorable clinical outcomes. This substantiates the need for a critical reevaluation of the FWS guideline and its indications for bacterial cultures, viral testing, and antibiotic treatment. WHAT IS KNOWN: • Despite the development of national guidelines, variation in practice is still substantial in the assessment of febrile children to distinguish severe infection from mild self-limiting disease. • Previous retrospective research suggests low adherence to national guidelines for febrile children in practice. WHAT IS NEW: • In case of non-adherence to the Dutch national guideline, similar to the National Institute for Health and Care Excellence (NICE) guideline from the United Kingdom, physicians have used fewer resources than the guideline recommended without increasing missed severe infections.

Cerebrospinal fluid inflammatory markers to differentiate between neonatal bacterial meningitis and sepsis: A prospective study of diagnostic accuracy.

OBJECTIVES: We evaluated the diagnostic accuracy of cerebrospinal fluid (CSF) inflammatory markers for diagnosing bacterial meningitis in neonates with sepsis and/or meningitis. METHODS: Cases were identified from a prospective multicenter study including patients aged 0-3 months with Group B Streptococcal (GBS) or Escherichia coli culture positive sepsis/meningitis. CSF CXCL10, MDC, IL-6, IL-8, IL-10, TNF- α, MIF, IL-1RA, CXCL13, IL-1ß, CRP and procalcitonin concentrations were measured with Luminex technology. RESULTS: In 61/373 patients (17%) residual CSF from the lumbar puncture was available, of whom 16 (26%) had definitive meningitis, 15 (25%) probable meningitis and 30 (49%) had sepsis. All biomarkers were detectable in CSF and showed significantly higher concentrations in definitive meningitis versus sepsis patients and six biomarkers in probable meningitis versus sepsis patients. Discrimination between definitive meningitis and sepsis was excellent for IL-1RA (area under the receiver operating characteristic curve [AUC] 0.93), TNF-α (AUC 0.92), CXCL10 (AUC 0.90), IL-1ß (AUC 0.92), IL-6 (AUC 0.94), IL-10 (AUC 0.93) and a combination of IL-1RA, TNF-α, CXCL-10 and CSF leukocyte count (AUC 0.95). CSF leukocyte count remained the predictor with the highest diagnostic accuracy (AUC 0.96). CONCLUSION: CSF inflammatory markers can be used to differentiate between neonatal sepsis and meningitis.

Long-term impact of serious neonatal bacterial infections on neurodevelopment.

BACKGROUND: Neonatal bacterial infections have long been recognized as an important cause of acute morbidity and mortality, but long-term neurodevelopmental consequences have not been comprehensively described and discussed. OBJECTIVES: We aimed to summarize evidence on the pathogenesis, diagnosis, and epidemiology of long-term sequelae after neonatal bacterial sepsis and meningitis. We also discuss approaches for future studies to quantify the public health impact of neonatal infection-associated neurodevelopmental impairment. SOURCES: We identified studies, both research articles and reviews, which provide mechanistic information on the long-term disease, as well as epidemiological studies that describe the frequency of neurodevelopmental impairment in children with and, for comparison, without a history of neonatal bacterial infection. Tools currently used in clinical practice and research settings to assess neurodevelopmental impairment were also reviewed. CONTENT: We first enumerate potential direct and indirect mechanisms that can lead to brain injury following neonatal infections. We then discuss summary data, either frequencies or measures of association, from epidemiological studies. Risk factors that predict long-term outcomes are also described. Finally, we describe clinical approaches for identifying children with neurodevelopmental impairment and provide an overview of common diagnostic tools. IMPLICATIONS: The limited number of studies that describe the long-term consequences of neonatal infections, often undertaken in high-income settings and using variable designs and diagnostic tools, are not sufficient to inform clinical practice and policy prioritization. Multi-country studies with follow-up into adolescence, standardized diagnostic approaches, and local comparator groups are needed, especially in low and middle-income countries where the incidence of neonatal sepsis is high.

Characteristics and prognostic factors of bacterial meningitis in the intensive care unit: a prospective nationwide cohort study.

BACKGROUND: Patients with bacterial meningitis can be severely ill necessitating intensive care unit (ICU) treatment. Here, we describe clinical features and prognostic factors of adults with bacterial meningitis admitted to the ICU in a nationwide prospective cohort study. METHODS: We prospectively assessed clinical features and outcome of adults (age > 16 years) with community-acquired bacterial meningitis included in the MeninGene study between March 1, 2006 and July 1, 2022, that were initially admitted to the ICU. We identified independent predictors for initial ICU admission and for unfavourable outcome (Glasgow Outcome Scale score between 1-4) by multivariable logistic regression. RESULTS: A total of 2709 episodes of bacterial meningitis were included, of which 1369 (51%) were initially admitted to the ICU. We observed a decrease in proportion of patients being admitted to the ICU during the Covid-19 pandemic in 2020 (decreased to 39%, p = 0.004). Median age of the 1369 patients initially admitted to the ICU was 61 years (IQR 49-69), and the rates of unfavourable outcome (47%) and mortality (22%) were high. During the Covid-19 pandemic, we observed a trend towards an increase in unfavourable outcome. Prognostic factors predictive for initial ICU admission were younger age, immunocompromised state, male sex, factors associated with pneumococcal meningitis, and those indicative of systemic compromise. Independent predictors for unfavourable outcome in the initial ICU cohort were advanced age, admittance to an academic hospital, cranial nerve palsies or seizures on admission, low leukocyte count in blood, high C-reactive protein in blood, low CSF: blood glucose ratio, listerial meningitis, need for mechanical ventilation, circulatory shock and persistent fever. 204 of 1340 episodes (15%) that were initially not admitted to the ICU were secondarily transferred to the ICU. The rates of unfavourable outcome (66%) and mortality (30%) in this group were high. CONCLUSIONS: The majority of patients with community-acquired bacterial meningitis are admitted to the ICU, and the unfavourable outcome and mortality rates of these patients remain high. Patients that are initially admitted to non-ICU wards but secondarily transferred to the ICU also had very high rates of unfavourable outcome.

Recurrent bacterial meningitis in children in the Netherlands: a nationwide surveillance study.

OBJECTIVES: This study aimed to estimate the recurrence rate of culture-positive bacterial meningitis in children in the Netherlands. DESIGN: Nationwide surveillance study, using the database of the Netherlands Reference Laboratory for Bacterial Meningitis to identify patients with culture-positive bacterial meningitis during childhood. SETTING: The study was based in the Netherlands. PARTICIPANTS: A total of 9731 children with a first bacterial meningitis episode between 1 July 1987 and 30 June 2019 were identified. PRIMARY AND SECONDARY OUTCOME MEASURES: Recurrence was defined as a subsequent episode >28 days, or caused by a different pathogen. Annual incidence and incidence rate ratios (IRRs) comparing the periods 1988-2003 and 2004-2019 were calculated. Predictors of recurrent meningitis were assessed using Cox proportional hazards regression. RESULTS: Sixty-three (0.6%) of the 9731 children with a first bacterial meningitis episode contracted recurrent meningitis. Neisseria meningitidis was the leading pathogen for first meningitis episodes (52%) and Streptococcus pneumoniae for recurrent episodes (52%). The median annual incidence of first episodes per 100 000 children decreased from 11.81 (IQR 11.26-17.60) in 1988-2003 to 2.60 (IQR 2.37-4.07) in 2004-2019 (IRR 0.25, 95% CI 0.23 to 0.26). The incidence of recurrences did not change: 0.06 (IQR 0.02-0.11) in 1988-2003 to 0.03 (IQR 0.00-0.06) in 2004-2019 (IRR 0.65, 95% CI 0.39 to 1.1). Age above 5 years (OR 3.6 (95% CI 1.5 to 8.3)) and a first episode due to Escherichia coli (OR 25.7 (95% CI 7.2 to 92.0)) were associated with higher risks of recurrence. CONCLUSION: The recurrence rate of childhood bacterial meningitis in the Netherlands was 0.6%. While the incidence rate of first episodes decreased substantially, this was not the case for recurrent episodes. Older age and a first episode due to E. coli were associated with higher recurrence risks.

Meeting report: Towards better risk stratification, prevention and therapy of invasive GBS disease, ESPID research meeting May 2022.

The European Society of Pediatric Infectious Diseases (ESPID) hosted the third Group B Streptococcus (GBS) Research Session in Athens on 11th May 2022, providing researchers and clinicians from around the world an opportunity to share and discuss recent advances in GBS pathophysiology, molecular and genetic epidemiology and how these new insights can help in improving prevention and control of early- and late-onset GBS disease. The meeting provided a state-of-the-art overview of the existing GBS prevention strategies and their limitations, and an opportunity to share the latest research findings. The first presentation provided an overview of current GBS prevention and treatment strategies. In the second presentation, the genomic and antimicrobial resistance profiles of invasive and colonizing GBS strains were presented. The third presentation explained the association of intrapartum antibiotic prophylaxis (IAP) with the development of late-onset disease (LOD) and the interplay of host innate immunity and GBS. The fourth presentation evaluated the role of genomics in understanding horizontal GBS transmission. The fifth presentation focused on the zoonotic links for certain GBS lineages and the last presentation described the protective role of breastmilk. Talks were followed with interactive discussions and concluded with recommendations on what is needed to further GBS clinical research; these included: (i) the development of better risk stratification methods by combining GBS virulence factors, serological biomarkers and clinical risk factors; (ii) further studies on the interplay of perinatal antimicrobials, disturbances in the development of host immunity and late-onset GBS disease; (iii) routine submission of GBS isolates to reference laboratories to help in detecting potential clusters by using genomic sequencing; (iv) collaboration in animal and human GBS studies to detect and prevent the emergence of new pathogenic sequence types; and (v) harnessing the plethora of immune factors in the breastmilk to develop adjunct therapies.

Epidemiology, clinical features and outcome of adults with meningococcal meningitis: a 15-year prospective nationwide cohort study.

Background: We describe the epidemiology, clinical features and outcome of adult meningococcal meningitis in the Netherlands over a 15-year period. Methods: We studied adults (age ≥ 16 years) who were listed by the Netherlands Reference Laboratory for Bacterial Meningitis and/or included in the prospective nationwide cohort study (MeninGene) between January 2006 and July 2021. Incidences were calculated per epidemiological year (July-June). Findings: We identified 442 episodes of adult meningococcal meningitis. The median patient age was 32 years (IQR 18-55) and 226 episodes (51%) occurred in female patients. The annual incidence per 100,000 adults fluctuated, from 0.33 in 2006-2007 to 0.05 in 2020-2021, with a temporal increase up to 0.30 from 2016 to 2018, driven by an outbreak of serogroup W (MenW). Of 442 episodes, 274 episodes (62%) in 273 patients were included in the clinical cohort study. The overall case fatality rate was 4% (10 of 274) and 16% (43 of 274) had an unfavourable outcome (Glasgow Outcome Scale score 1-4). Compared to other serogroups, MenW was associated with higher rates of unfavourable outcome (6 of 16 [38%] vs. 37 of 251 [15%], P = 0.03) and death (4 of 16 [25%] vs. 6 of 251 [2%], P = 0.001). Interpretation: The overall incidence of adult meningococcal meningitis in the Netherlands is low and outcome is generally favourable. An increase of MenW meningitis occurred from 2016 to 2018, which was associated with more unfavourable outcome and death. Funding: Netherlands Organisation for Health Research and Development, European Research Council, National Institute of Public Health and Environmental protection.

Group B Streptococcus Early-Onset Disease: New Preventive and Diagnostic Tools to Decrease the Burden of Antibiotic Use.

The difficulty in recognizing early-onset neonatal sepsis (EONS) in a timely manner due to non-specific symptoms and the limitations of diagnostic tests, combined with the risk of serious consequences if EONS is not treated in a timely manner, has resulted in a low threshold for starting empirical antibiotic treatment. New guideline strategies, such as the neonatal sepsis calculator, have been proven to reduce the antibiotic burden related to EONS, but lack sensitivity for detecting EONS. In this review, the potential of novel, targeted preventive and diagnostic methods for EONS is discussed from three different perspectives: maternal, umbilical cord and newborn perspectives. Promising strategies from the maternal perspective include Group B Streptococcus (GBS) prevention, exploring the virulence factors of GBS, maternal immunization and antepartum biomarkers. The diagnostic methods obtained from the umbilical cord are preliminary but promising. Finally, promising fields from the newborn perspective include biomarkers, new microbiological techniques and clinical prediction and monitoring strategies. Consensus on the definition of EONS and the standardization of research on novel diagnostic biomarkers are crucial for future implementation and to reduce current antibiotic overexposure in newborns.

A risk score for identifying patients at a low risk of bacterial meningitis amongst adults with cerebrospinal fluid leucocytosis and a negative gram stain result: a derivation and validation study.

OBJECTIVES: We aimed to derive and validate a risk score to differentiate patients with bacterial meningitis from those with viral meningitis or encephalitis amongst patients presenting with cerebrospinal fluid (CSF) leucocytosis and a negative Gram staining result. METHODS: We included adults with bacterial and viral meningitis or encephalitis presenting with CSF leukocyte counts of >10 per mm3 and a negative Gram staining result from cohorts in Houston, Texas (2004-2019), and the Netherlands (2012-2021). Derivation and the first validation were performed in the American patients and further validation in the Dutch patients. RESULTS: Derivation was performed in 109 American patients with bacterial meningitis (median age, 56 years; interquartile range [IQR], 46-66 years; 46% women) and 194 with viral meningitis or encephalitis (median age, 46 years; IQR, 33-60 years; 53% women). Serum leukocyte counts of >10.0 × 109/L, CSF leukocyte counts of >2000 per mm3, granulocyte counts of >1180 per mm3, protein levels of >2.2 g/L, glucose levels of <1.9 mmol/L and fever on admission were included in the risk score, which was dichotomized into 'low risk' (0 present) and 'high risk' (>0 present). The first validation showed a sensitivity of 100% (95% CI, 96.6-100) and specificity of 34.0% (95% CI, 27.4-41.2). Further validation in 262 Dutch patients with bacterial meningitis (median age, 57 years; IQR 44-70 years; 45% women) and 68 with viral meningitis (median age, 34 years; IQR, 28-45 years; 60% women) showed a sensitivity of 99.6% (95% CI, 97.9-100) and specificity of 41.2% (95% CI, 29.4-53.7). CONCLUSIONS: Our risk score may be able to rule out bacterial meningitis amongst patients presenting with CSF leucocytosis and a negative Gram staining result. However, it needs prospective testing prior to clinical implementation.

Current treatment practice of functional abdominal pain disorders in children: A multicenter survey.

BACKGROUND: Approximately 90% of the children with chronic abdominal pain are diagnosed as having functional abdominal pain disorder (FAPD). The Dutch guideline "functional abdominal pain" provides a stepwise approach to treat FAPD. The aim of this survey was twofold first, to determine adherence to the Dutch guideline, and second to determine current management of FAPDs in clinical practice. METHODS: A multicenter survey was designed. The survey was sent to pediatricians and pediatric residents in December 2020. The study ran from October 2020 until March 2021. Participants in ten hospitals in the western region of The Netherlands were invited to complete this survey. Respondents who indicated not to treat children with FAPDs or respondents who completed less than 3 steps of the survey were excluded. RESULTS: In total, 85/174 (48.9%) respondents completed the survey. We included 80 respondents, 68 pediatricians and 12 pediatric residents, for analysis. Overall, self-reported guideline adherence was 85%. Self-reported adherence was higher than actual adherence. Only 50% of all respondents followed the first three steps of the guideline. The reported non-pharmacological and pharmacological treatments were diverse and varied between different age groups. The average follow-up duration was between 2 and 6 months, and the most regularly used outcome measures were attendance at school, quality of life, and adequate pain relief/reassurance. CONCLUSION: We reportedly observed a large variation in the management of children with FAPDs, due to low guideline adherence among clinicians. Improved guideline adherence may be accomplished by updating the guideline with specific recommendations per subtype, follow-up and outcome measures as well measures to improve guideline implementation.

Differences in systemic and mucosal SARS-CoV-2 antibody prevalence in a prospective cohort of Dutch children.

Background: As SARS-CoV-2 will likely continue to circulate, low-impact methods become more relevant to monitor antibody-mediated immunity. Saliva sampling could provide a non-invasive method with reduced impact on children. Studies reporting on the differences between systemic and mucosal humoral immunity to SARS-CoV-2 are inconsistent in adults and scarce in children. These differences may be further unraveled by exploring associations to demographic and clinical variables. Methods: To evaluate the use of saliva antibody assays, we performed a cross-sectional cohort study by collecting serum and saliva of 223 children attending medical services in the Netherlands (irrespective of SARS-CoV-2 exposure, symptoms or vaccination) from May to October 2021. With a Luminex and a Wantai assay, we measured prevalence of SARS-CoV-2 spike (S), receptor binding domain (RBD) and nucleocapsid-specific IgG and IgA in serum and saliva and explored associations with demographic variables. Findings: The S-specific IgG prevalence was higher in serum 39% (95% CI 32 - 45%) than in saliva 30% (95% CI 24 - 36%) (P ≤ 0.003). Twenty-seven percent (55/205) of children were S-specific IgG positive in serum and saliva, 12% (25/205) were only positive in serum and 3% (6/205) only in saliva. Vaccinated children showed a higher concordance between serum and saliva than infected children. Odds for saliva S-specific IgG positivity were higher in girls compared to boys (aOR 2.63, P = 0.012). Moreover, immunocompromised children showed lower odds for S- and RBD-specific IgG in both serum and saliva compared to healthy children (aOR 0.23 - 0.25, P ≤ 0.050). Conclusions: We showed that saliva-based antibody assays can be useful for identifying SARS-CoV-2 humoral immunity in a non-invasive manner, and that IgG prevalence may be affected by sex and immunocompromisation. Differences between infection and vaccination, between sexes and between immunocompromised and healthy children should be further investigated and considered when choosing systemic or mucosal antibody measurement.

Identification of a Novel CYP11B2 Variant in a Family with Varying Degrees of Aldosterone Synthase Deficiency.

Isolated aldosterone synthase deficiency is a rare autosomal recessive disorder caused by pathogenic variants in CYP11B2, resulting in impaired aldosterone synthesis. We report on a neonate with isolated aldosterone synthase deficiency caused by a novel homozygous CYP11B2 variant Chr8:NM_000498.3:c.400G>A p.(Gly134Arg). The patient presented shortly after birth with severe signs of aldosterone deficiency. Interestingly, segregation analysis revealed that the patient's asymptomatic father was also homozygous for the CYP11B2 variant. Biochemical evaluation of the father indicated subclinical enzyme impairment, characterized by elevated aldosterone precursors. Apparently, this homozygous variant led to different clinical phenotypes in two affected relatives. In this manuscript we elaborate on the performed biochemical and genetic work-up and describe potential pitfalls of CYP11B2 sequencing due to its homology to CYP11B2.

Short-term and long-term risk of mortality and neurodevelopmental impairments after bacterial meningitis during infancy in children in Denmark and the Netherlands: a nationwide matched cohort study.

BACKGROUND: Few studies have reported the long-term consequences of bacterial meningitis during infancy, and studies that have been done usually do not include a comparison cohort. We aimed to assess short-term and long-term risk of mortality, neurodevelopmental impairment (NDI), and health-care use and household income in cohorts of children with and without a history of bacterial meningitis during infancy in Denmark and the Netherlands. METHODS: In this nationwide cohort study, infants with a history of bacterial meningitis before age 1 year were identified through the Danish Medical Birth Registry and Danish National Patient Registry using International Classification of Diseases (ICD)-10 codes and through the Netherlands Reference Laboratory for Bacterial Meningitis. Infants were matched (1:10) by sex and birth month and year to a comparison cohort of the general population without a history of bacterial meningitis. We analysed mortality using Cox proportional hazards regression. In Denmark, diagnoses of NDIs were based on ICD-10 codes; in the Netherlands, special educational needs were used as a functional NDI outcome. Risk ratios (RRs) of NDIs were estimated using modified Poisson regression. We also analysed long-term health-care use in Denmark and household income in both countries. All regression analyses were adjusted for sex and year of birth, and stratified by pathogen whenever sample size allowed. FINDINGS: We included 2216 children with a history of bacterial meningitis (570 [25·7%] in Denmark between Jan 1, 1997, and Dec 31, 2018, and 1646 [74·3%] in the Netherlands between Jan 1, 1995, and Dec 31, 2018), matched to 22 127 comparison cohort members. Median age at diagnosis was 2·8 months (IQR 0·4-7·1) in Denmark and 4·3 months (0·7-7·4) in the Netherlands. Mortality risks within 3 months after disease onset were 3·9% (95% CI 2·6-5·8%) in Denmark and 5·9% (4·7-7·0) in the Netherlands, compared with 0·0% (p<0·0001) and 0·1% (p<0·0001) in the comparison cohorts. Survivors had an increased risk of moderate or severe NDIs at age 10 years (RR 5·0 [95% CI 3·5-7·1] in Denmark and 4·9 [4·0-6·2] in the Netherlands) compared to children in the comparison cohort, particularly after pneumococcal and group B streptococcal meningitis. In Denmark, a history of bacterial meningitis was associated with increased health-care use in the 10 years following diagnosis (rate ratio 4·5 [95% CI 3·9-5·2] for outpatient visits and 4·1 [3·6-4·7] for hospital admissions). INTERPRETATION: Our study shows increased risk of mortality in the short and long term, a five times increase in risk of NDIs, and increased health-care use after bacterial meningitis during infancy. Together with context-specific incidence data, our results can advance pathogen-specific estimation of the meningitis burden and inform service provision at the individual and population level. FUNDING: Bill & Melinda Gates Foundation, the Stichting Remmert Adriaan Laan Fonds, and the Netherlands Organisation for Health Research and Development.

Population genomics of Group B Streptococcus reveals the genetics of neonatal disease onset and meningeal invasion.

Group B Streptococcus (GBS), or Streptococcus agalactiae, is a pathogen that causes preterm births, stillbirths, and acute invasive neonatal disease burden and mortality. Here, we investigate bacterial genetic signatures associated with disease onset time and meningeal tissue infection in acute invasive neonatal GBS disease. We carry out a genome-wide association study (GWAS) of 1,338 GBS isolates from newborns with acute invasive disease; the isolates had been collected annually, for 30 years, through a national bacterial surveillance program in the Netherlands. After controlling for the population structure, we identify genetic variation within noncoding and coding regions, particularly the capsule biosynthesis locus, statistically associated with neonatal GBS disease onset time and meningeal invasion. Our findings highlight the impact of integrating microbial population genomics and clinical pathogen surveillance, and demonstrate the effect of GBS genetics on disease pathogenesis in neonates and infants.

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

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.