Is vaccination against measles, mumps, and rubella associated with reduced rates of antibiotic treatments among children below the age of 2 years? Nationwide register-based study from Denmark, Finland, Norway, and Sweden.

OBJECTIVES: Previous studies have shown that vaccination against measles, mumps, and rubella (MMR) may have beneficial non-specific effects, reducing the risk of infections not targeted by the vaccine. We investigated if MMR vaccine given after the third dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP3), was associated with reduced rates of antibiotic treatments. METHODS: Register-based cohort study following children from the age of recommended MMR vaccination until age 2 years. We included 831,287 children born in Denmark, Finland, Norway, and Sweden who had received DTaP3 but not yet MMR vaccine. Cox proportional hazards regression with age as the underlying timescale and vaccination status as a time-varying exposure was used to estimate covariate-adjusted Hazard Ratios (aHRs) and inverse probability of treatment weighted (IPTW) HRs of antibiotic treatments. Summary estimates were calculated using random-effects meta-analysis. RESULTS: Compared with only having received DTaP3, receipt of MMR vaccine after DTaP3 was associated with reduced rates of antibiotic treatments in all countries: the aHR was 0.92 (0.91-0.93) in Denmark, 0.92 (0.90-0.94) in Finland, 0.84 (0.82-0.85) in Norway, and 0.87 (0.85-0.90) in Sweden, yielding a summary estimate of 0.89 (0.85-0.93). A stronger beneficial association was seen in a negative control exposure analysis comparing children vaccinated with DTaP3 vs two doses of DTaP. CONCLUSIONS: Across the Nordic countries, receipt of MMR vaccine after DTaP3 was associated with an 11% lower rate of antibiotic treatments. The negative control analysis suggests that the findings are affected by residual confounding. Findings suggest that potential non-specific effects of MMR vaccine are of limited clinical and public health importance for the milder infections treated out-of-hospital in the Nordic setting.

Cohort Profile: Childhood morbidity and potential non-specific effects of the childhood vaccination programmes in the Nordic countries (NONSEnse): register-based cohort of children born 1990-2017/2018.

PURPOSE: The aim of the NONSEnse project is to investigate the non-specific effects of vaccines and immunisation programmes on the overall health of children by using information from the extensive nationwide registers on health and sociodemographic factors in Denmark, Finland, Norway and Sweden. PARTICIPANTS: The cohort covers 9 072 420 children aged 0-17 years, born 1990-2017/2018 and living in Denmark, Finland, Norway or Sweden. All countries use a unique identification number for its permanent residents, which makes it possible to link individual-level information from different registers. FINDINGS TO DATE: Data collection and harmonisation according to a common data model was completed in March 2022. As a prerequisite for comparing the effects of childhood vaccinations on the overall health of children across the Nordic countries, we have identified indicators measuring similar levels of infectious disease morbidity across these settings. So far, studies pertaining to non-specific effects of vaccines are limited to investigations that could be undertaken using aggregated data sets that were available before the NONSEnse cohort with individual-level information was completely set up. FUTURE PLANS: We are currently performing several studies of the effects on non-targeted infectious disease morbidity across the countries following vaccination against measles, mumps, rubella, diphtheria, tetanus, pertussis, human papillomavirus, rotavirus and influenza. Multiple studies are planned within the next years using different study designs to facilitate triangulation of results and enhance causal inference. REGISTRATION: No clinical trials will be conducted within the NONSEnse project.

Trends in Antibiotic Use in Danish, Finnish, Norwegian and Swedish Children.

Objective: To compare the use of antibiotics in children in four Northern European countries. Methods: We conducted a register-based study based on individual-level prescription data from national prescription registers. We identified all redeemed outpatient prescriptions for systemic antibiotics in children aged 0-14 years from July 2006 to June 2017 in Denmark, Finland, Norway, and Sweden. We computed incidence rates and incidence rate ratios of treatment episodes with any antibiotic and different antibiotic classes. Results: In 2016/2017, the rates of antibiotic treatment episodes per 1000 person-years in children aged 0-14 years were 429, 284, 219, and 184 in Finland, Denmark, Sweden, and Norway, respectively, and the rate ratios (95% confidence intervals) compared with Norway were 2.33 (2.33-2.34), 1.54 (1.54-1.55), and 1.19 (1.19-1.20) in Finland, Denmark, and Sweden, respectively. The rate of antibiotic treatment episodes declined over time in all countries. The relative reductions in 2016/2017 compared with 2006/2007 were 36% in Finland, 40% in Denmark, 49% in Sweden, and 29% in Norway. Treatment episodes peaked between age 12 and 18 months. The most used antibiotic class was beta-lactamase sensitive penicillins among all children in Norway and Sweden and among children above two years in Denmark, while penicillins with extended spectrum were most used in Finland and among the youngest children in Denmark. Conclusion: In all countries, the use of antibiotics in children declined between 2006 and 2017. However, there were still considerable differences in antibiotic use between otherwise quite similar Nordic countries, with a more than 2-fold difference between the countries with the lowest and highest rates. Interventions to reduce the number of antibiotic treatment episodes in the countries with higher rates could reduce the total antibiotic use.

Hospital Contacts for Infectious Diseases Among Children in Denmark, Finland, Norway, and Sweden, 2008-2017.

Purpose: Comparing rates of childhood infectious disease hospitalisations across countries may uncover areas for improvement in the prevention of severe childhood infections. We compared rates of childhood infectious disease hospital contacts across Denmark, Finland, Norway, and Sweden with the overall objective to elucidate potential differences in burden of disease and in organisational and registration practices. Methods: Using national registries, we estimated incidence rates for infectious disease hospital contacts between 2008 and 2017 among children aged 0-14 years. We investigated the rates for different types of contacts (inpatient or outpatient including emergency room), duration of admission, and by sex. Results: During the study period, the rate of all hospital contacts per 1000 person-years was highest in Sweden (125.2) followed by Finland (87.1), Denmark (79.0), and Norway (62.1). The rates aligned for inpatient contacts with overnight stays; 19.3 (Denmark), 16.6 (Finland), 16.3 (Norway), and 13.0 (Sweden); these were highest in early infancy in all countries. A peak around 1 year of age was seen in all countries except in Sweden. The rates were higher among boys compared with girls in early childhood, after 13 years of age the rates among girls surpassed the boys. Conclusion: Large cross-country differences were observed for outpatient and short-term hospital contacts for infectious diseases, affected by differences in organisational structures and coding practices across and within countries over time. Inpatient contacts requiring overnight stays reflected more comparable levels of severe infections across countries. Childhood infectious disease morbidity was greatest among boys and before 2 years of age.

Revaccination with measles-mumps-rubella vaccine and hospitalization for infection in Denmark and Sweden - An interrupted time-series analysis.

BACKGROUND: In a previous cohort study of 4-year-old Danish children, revaccination with the live measles-mumps-rubella vaccine (MMR) was associated with a 16% reduction in the rate of hospitalization lasting two days or longer for non-measles-mumps-rubella infections. AIM: To examine if the introduction of revaccination with MMR at 4 years of age in Denmark (spring 2008) and at 7-9 years of age in Sweden (autumn 2009), at a time when there was virtually no measles, mumps or rubella cases, was associated with a reduction in the rate of hospitalization-for-infection lasting two days or longer at the population level. METHODS: We included 4-year-olds in Denmark and 7-9-year-olds in Sweden. We obtained the number of hospitalization-for-infection lasting two days or longer from nationwide hospital registers. Person-years at risk were approximated from population statistics for each season and year. We performed an interrupted time series analysis using Poisson regression to estimate the change in hospitalization incidence rates following the introduction of MMR revaccination, adjusting for seasonality. We also performed analyses with control series (3-year-olds in Denmark and 4-year-olds in Sweden). RESULTS: Comparing the incidence of hospitalization-for-infection lasting two days or longer after the introduction of MMR revaccination with the expected level without an introduction of MMR revaccination resulted in an incidence rate ratio of 1.07 (95% confidence interval [CI] = 0.89-1.28) for 4-year-olds in Denmark and 0.89 (95% CI = 0.77-1.02) for 7-9-year-olds in Sweden in analyses without controls. Analyses with controls gave similar results. CONCLUSION: This population-level study of the introduction of MMR revaccination in Denmark and Sweden had inadequate power to confirm or refute the findings from an individual-level Danish study of an association between MMR revaccination and a lower incidence rate of hospitalization-for-infection lasting two days or longer.

Timeliness of DTaP-IPV-Hib Vaccination and Development of Atopic Dermatitis Between 4 Months and 1 Year of Age-Register-Based Cohort Study.

BACKGROUND: An Australian study including 4433 children found that delayed Diphtheria-Tetanus-acellular Pertussis-containing vaccination was associated with reduced risk of developing atopic dermatitis (AD) before age 1 year. OBJECTIVE: We assessed whether delayed vaccination against diphtheria, tetanus, acellular pertussis, polio, and Haemophilus influenzae type b (Diphtheria, Tetanus, acellular Pertussis - Inactivated Polio vaccine - Haemophilus influenzae type b [DTaP]) was associated with a reduced risk of new cases of AD before age 1 year in Denmark. METHODS: We used nationwide registers to follow 883,160 children born in Denmark from 1997 to 2012. Binary regression models adjusting for potential confounding factors were applied to estimate relative risks (adjusted relative risks [aRRs]) of developing AD among children with delayed DTaP vaccination (defined as given 1 month or more after the recommended age) compared with timely vaccinated children. RESULTS: Among 143,429 children with a delayed first dose of DTaP, 4,847 (3.4%) developed AD between age 4 months and 1 year, compared with 27,628 (3.7%) among 739,731 children not having delayed DTaP (aRR 0.94; 95% CI, 0.91-0.97). The aRR was 0.94 (95% CI, 0.90-0.99) for children with a delayed second dose, and the aRR was 0.88 (95% CI, 0.82-0.93) when comparing children with delayed first and second doses with all timely vaccinated children. CONCLUSIONS: The results support the hypothesis that delayed vaccination with DTaP is associated with reduced risk of developing new cases of AD after age 4 months. The dose-dependent relationship strengthens the evidence of a causal relationship. Some countries are introducing maternal pertussis vaccination and delaying the first dose of DTaP, providing a possibility for further testing the hypothesis.

Hospitalizations for infections by age and sex: register-based study of Danish children 1977-2014.

Background: Infectious diseases are a major cause of hospitalizations in children and there is increasing interest in sex differences in immunity during childhood. Therefore, we examined hospital admission rates for infectious diseases in Danish children by age and sex.Methods: Register-based cohort study of all Danish residents aged 0-14 years from 1977 to 2014. We examined total admission rate for infections and rates of admission by types of infection.Results: This study included 3,689,999 children and 1,080,750 admissions for infections. The admission rates peaked at age 0 months (boys, 197.9 admissions per 1000 person-years; girls, 160.9) and age 11 months (boys, 155.5; girls, 113.9). The male-female ratio of admissions was 1.25 for children aged 0-14 years, but varied by age and type of infection. Boys had the highest admission rate for any infection until 9 years of age after which girls had a higher rate. Boys had higher admission rates for gastrointestinal infections and lower respiratory tract infections than girls at all ages. The admission rates for upper respiratory tract infections and 'Other infections' for girls were higher than the rates for boys at age 10 and 4 years, respectively.Conclusions: Overall, boys had around 25% higher admission rates for infections than girls, with some variation according to age and type of infection.