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.

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.

Model-based assessment of the safety of community interventions with primaquine in sub-Saharan Africa.

BACKGROUND: Single low-dose primaquine (SLD-PQ) is recommended in combination with artemisinin-based combination therapy to reduce Plasmodium falciparum transmission in areas threatened by artemisinin resistance or aiming for malaria elimination. SLD-PQ may be beneficial in mass drug administration (MDA) campaigns to prevent malaria transmission but uptake is limited by concerns of hemolysis in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. The aim of this study was to improve the evidence on the safety of MDA with SLD-PQ in a sub-Saharan African setting. METHODS: A nonlinear mixed-effects model describing the pharmacokinetics and treatment-induced hemolysis of primaquine was developed using data from an adult (n = 16, G6PD deficient) and pediatric study (n = 38, G6PD normal). The relationship between primaquine pharmacokinetics and hemolysis was modeled using an established erythrocyte lifespan model. The safety of MDA with SLD-PQ was explored through Monte Carlo simulations for SLD-PQ at 0.25 or 0.4 mg/kg using baseline data from a Tanzanian setting with detailed information on hemoglobin concentrations and G6PD status. RESULTS: The predicted reduction in hemoglobin levels following SLD-PQ was small and returned to pre-treatment levels after 25 days. G6PD deficiency (African A- variant) was associated with a 2.5-fold (95% CI 1.2-8.2) larger reduction in hemoglobin levels. In the Tanzanian setting where 43% of the population had at least mild anemia (hemoglobin < 11-13 g/dl depending on age and sex) and 2.73% had severe anemia (hemoglobin < 7-8 g/dl depending on age and sex), an additional 3.7% and 6.0% of the population were predicted to develop at least mild anemia and 0.25% and 0.41% to develop severe anemia after 0.25 and 0.4 mg/kg SLD-PQ, respectively. Children < 5 years of age and women ≥ 15 years of age were found to have a higher chance to have low pre-treatment hemoglobin. CONCLUSIONS: This study supports the feasibility of MDA with SLD-PQ in a sub-Saharan African setting by predicting small and transient reductions in hemoglobin levels. In a setting where a substantial proportion of the population had low hemoglobin concentrations, our simulations suggest treatment with SLD-PQ would result in small increases in the prevalence of anemia which would most likely be transient.

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.

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.

A review of the costs of delivering maternal immunisation during pregnancy.

BACKGROUND: Routine maternal immunisation against influenza and pertussis are recommended by the WHO to protect mother and child, and new vaccines are under development. Introducing maternal vaccines into national programmes requires an understanding of vaccine delivery costs - particularly in low resource settings. METHODS: We searched Medline, Embase, Econlit, and Global Health for studies reporting costs of delivering vaccination during pregnancy but excluded studies that did not separate the vaccine purchase price. Extracted costs were inflated and converted to 2018 US dollars. RESULTS: Sixteen studies were included, of which two used primary data to estimate vaccine delivery costs. Costs per dose ranged from $0.55 to $0.64 in low-income countries, from $1.25 to $6.55 for middle-income countries, and from $5.76 to $39.87 in high-income countries. CONCLUSIONS: More research is needed on the costs of delivering maternal immunisation during pregnancy, and of integrating vaccine delivery into existing programmes of antenatal care especially in low and middle-income countries.

Quantifying long-term health and economic outcomes for survivors of group B Streptococcus invasive disease in infancy: protocol of a multi-country study in Argentina, India, Kenya, Mozambique and South Africa.

Sepsis and meningitis due to invasive group B Streptococcus (iGBS) disease during early infancy is a leading cause of child mortality. Recent systematic estimates of the worldwide burden of GBS suggested that there are 319,000 cases of infant iGBS disease each year, and an estimated 147,000 stillbirths and young-infant deaths, with the highest burden occurring in Sub-Saharan Africa.  The following priority data gaps were highlighted: (1) long-term outcome data after infant iGBS, including mild disability, to calculate quality-adjusted life years (QALYs) or disability-adjusted life years (DALYs) and (2) economic burden for iGBS survivors and their families. Geographic data gaps were also noted with few studies from low- and middle- income countries (LMIC), where the GBS burden is estimated to be the highest. In this paper we present the protocol for a multi-country matched cohort study designed to estimate the risk of long-term neurodevelopmental impairment (NDI), socioemotional behaviors, and economic outcomes for children who survive invasive GBS disease in Argentina, India, Kenya, Mozambique, and South Africa. Children will be identified from health demographic surveillance systems, hospital records, and among participants of previous epidemiological studies. The children will be aged between 18 months to 17 years. A tablet-based custom-designed application will be used to capture data from direct assessment of the child and interviews with the main caregiver. In addition, a parallel sub-study will prospectively measure the acute costs of hospitalization due to neonatal sepsis or meningitis, irrespective of underlying etiology. In summary, these data are necessary to characterize the consequences of iGBS disease and enable the advancement of effective strategies for survivors to reach their developmental and economic potential. In particular, our study will inform the development of a full public health value proposition on maternal GBS immunization that is being coordinated by the World Health Organization.

High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension.

Sickle cell disease (SCD) is caused by a variant hemoglobin molecule that polymerizes inside red blood cells (RBCs) in reduced oxygen tension. Treatment development has been slow for this typically severe disease, but there is current optimism for curative gene transfer strategies to induce expression of fetal hemoglobin or other nonsickling hemoglobin isoforms. All SCD morbidity and mortality arise directly or indirectly from polymer formation in individual RBCs. Identifying patients at highest risk of complications and treatment candidates with the greatest curative potential therefore requires determining the amount of polymer in individual RBCs under controlled oxygen. Here, we report a semiquantitative measurement of hemoglobin polymer in single RBCs as a function of oxygen. The method takes advantage of the reduced oxygen affinity of hemoglobin polymer to infer polymer content for thousands of RBCs from their overall oxygen saturation. The method enables approaches for SCD treatment development and precision medicine.