Risk of Type 1 Diabetes in Children Is Not Increased After SARS-CoV-2 Infection: A Nationwide Prospective Study in Denmark.

OBJECTIVE: It has been hypothesized that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children can increase risk of developing type 1 diabetes. RESEARCH DESIGN AND METHODS: We undertook a prospective, register-based analysis of children in Denmark by investigating the association between SARS-CoV-2 infection and subsequent risk of type 1 diabetes. During the pandemic, Denmark had one of the highest test rates per capita in the world, and 90% of all Danish children were tested. RESULTS: Compared with children with a history of only negative SARS-CoV-2 tests, we did not observe a higher risk of first-time diagnosis of type 1 diabetes in children 30 days or more after a positive SARS-CoV-2 test (hazard ratio 0.85; 95% CI 0.70-1.04). CONCLUSIONS: Our data do not support that SARS-CoV-2 infection is associated with type 1 diabetes or that type 1 diabetes should be a special focus after a SARS-CoV-2 infection in children.

The impact of the COVID-19 lockdown on birthweight among singleton term birth in Denmark.

In Denmark, a nationwide COVID-19 lockdown was implemented on March 12, 2020 and eased on April 14, 2020. The COVID-19 lockdown featured reduced prevalence of extremely preterm or extremely low birthweight births. This study aims to explore the impact of this COVID-19 lockdown on term birthweights in Denmark. We conducted a nationwide register-based cohort study on 27,870 live singleton infants, born at term (weeks 37-41), between March 12 and April 14, 2015-2020, using data from the Danish Neonatal Screening Biobank. Primary outcomes, corrected for confounders, were birthweight, small-for-gestational-age (SGA), and large-for-gestational-age (LGA), comparing the COVID-19 lockdown to the previous five years. Data were analysed using linear regression to assess associations with birthweight. Multinomial logistic regression was used to assess associations with relative-size-for-gestational-age (xGA) categories. Adjusted mean birthweight was significantly increased by 16.9 g (95% CI = 4.1-31.3) during the lockdown period. A dip in mean birthweight was found in gestational weeks 37 and 38 balanced by an increase in weeks 40 and 41. The 2020 lockdown period was associated with an increased LGA prevalence (aOR 1.13, 95% CI = 1.05-1.21). No significant changes in proportions of xGA groups were found between 2015 and 2019. The nationwide COVID-19 lockdown resulted in a small but significant increase in birthweight and proportion of LGA infants, driven by an increase in birthweight in gestational weeks 40 and 41.

Clinical outcomes of myocarditis after SARS-CoV-2 mRNA vaccination in four Nordic countries: population based cohort study

Objective To investigate the clinical outcomes of myocarditis associated with mRNA vaccines against the SARS-CoV-2 virus compared with other types of myocarditis. Design Population based cohort study. Setting Nationwide register data from four Nordic countries (Denmark, Finland, Norway, and Sweden), from 1 January 2018 to the latest date of follow-up in 2022. Participants The Nordic myocarditis cohort;7292 individuals aged ≥12 years who had an incident diagnosis of myocarditis as a main or secondary diagnosis, in a population of 23 million individuals in Denmark, Finland, Norway, and Sweden. Main outcome measures Heart failure, or death from any cause within 90 days of admission to hospital for new onset myocarditis, and hospital readmission within 90 days of discharge to hospital for new onset myocarditis. Clinical outcomes of myocarditis associated with SARS-CoV-2 mRNA vaccination, covid-19 disease, and conventional myocarditis were compared. Results In 2018-22, 7292 patients were admitted to hospital with new onset myocarditis, with 530 (7.3%) categorised as having myocarditis associated with SARS-CoV-2 mRNA vaccination, 109 (1.5%) with myocarditis associated with covid-19 disease, and 6653 (91.2%) with conventional myocarditis. At the 90 day follow-up, 62, nine, and 988 patients had been readmitted to hospital in each group (vaccination, covid-19, and conventional myocarditis groups, respectively), corresponding to a relative risk of readmission of 0.79 (95% confidence interval 0.62 to 1.00) and 0.55 (0.30 to 1.04) for the vaccination type and covid-19 type myocarditis groups, respectively, compared with the conventional myocarditis group. At the 90 day follow-up, 27, 18, and 616 patients had a diagnosis of heart failure or died in the vaccination type, covid-19 type, and conventional myocarditis groups, respectively. The relative risk of heart failure within 90 days was 0.56 (95% confidence interval 0.37 to 0.85) and 1.48 (0.86 to 2.54) for myocarditis associated with vaccination and covid-19 disease, respectively, compared with conventional myocarditis;the relative risk of death was 0.48 (0.21 to 1.09) and 2.35 (1.06 to 5.19), respectively. Among patients aged 12-39 years with no predisposing comorbidities, the relative risk of heart failure or death was markedly higher for myocarditis associated with covid-19 disease than for myocarditis associated with vaccination (relative risk 5.78, 1.84 to 18.20). Conclusions Compared with myocarditis associated with covid-19 disease and conventional myocarditis, myocarditis after vaccination with SARS-CoV-2 mRNA vaccines was associated with better clinical outcomes within 90 days of admission to hospital.

Cardiac Characteristics of the First Two Waves of COVID-19 in Denmark and the Prognostic Value of Echocardiography: The ECHOVID-19 Study.

INTRODUCTION: COVID-19 has spread globally in waves, and Danish treatment guidelines have been updated following the first wave. We sought to investigate whether the prognostic values of echocardiographic parameters changed with updates in treatment guidelines and the emergence of novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, 20E (EU1) and Alpha (B.1.1.7), and further to compare cardiac parameters between patients from the first and second wave. METHODS: A total of 305 patients hospitalised with COVID-19 were prospectively included, 215 and 90 during the first and second wave, respectively. Treatment in the study was defined as treatment with remdesivir, dexamethasone, or both. Patients were assumed to be infected with the dominant SARS-CoV-2 variant at the time of their hospitalisation. RESULTS: Mean age for the first vs. second wave was 68.7±13.6 vs. 69.7±15.8 years and 55% vs. 62% were male. Left ventricular (LV) systolic and diastolic function was worse in patients hospitalised during the second wave (LV ejection fraction (LVEF) for first vs. second wave = 58.5±8.1% vs. 52.4±10.6%, p<0.001) and global longitudinal strain (GLS) = 16.4±4.3% vs. 14.2±4.3%, p<0.001). In univariable cox regressions, reduced LVEF (HR=1.07 per 1% decrease, p=0.002), GLS (HR=1.21 per 1% decrease, p<0.001), and TAPSE (HR=1.18 per 1mm decrease, p<0.001) were associated with covid-related mortality, but only GLS remained significant in fully adjusted analysis (HR=1.14, p=0.02). CONCLUSION: Reduced GLS was associated with covid-related mortality independently of wave, treatment, and SARS-CoV-2 variant. LV function was significantly impaired in patients hospitalised during the second wave.

Vitamin D status and severity of COVID-19.

We explored the association between COVID-19 severity and vitamin D status using information from Danish nation-wide health registers, the COVID-19 surveillance database and stored blood samples from the national biobank. 25-hydroxyvitamin D (25(OH)D) was measured using tandem mass spectroscopy. The association between 25(OH)D levels and COVID-19 severity, classified hierarchical as non-hospitalized, hospitalized but not admitted to an intensive care unit (ICU), admitted to ICU, and death, was evaluated by proportional odds ratios (POR) assuming proportionality between the four degrees of severity. Among 447 adults tested SARS-CoV-2 positive in the spring of 2020, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. Thus, odds of experiencing more severe COVID-19 among individuals with insufficient (25 to < 50 nmol/L) and sufficient (≥ 50 nmol/L) 25(OH)D levels were approximately 50% of that among individuals with deficient levels (< 25 nmol/L) (POR = 0.49 (95% CI 0.25-0.94), POR = 0.51 (95% CI 0.27-0.96), respectively). Dividing sufficient vitamin D levels into 50 to < 75 nmol/L and ≥ 75 nmol/L revealed no additional beneficial effect of higher 25(OH)D levels. In this observational study, low levels of 25(OH)D were associated with a higher risk of severe COVID-19. A possible therapeutic role of vitamin D should be evaluated in well-designed interventional studies.

A nationwide questionnaire study of post-acute symptoms and health problems after SARS-CoV-2 infection in Denmark.

A considerable number of individuals infected with SARS-CoV-2 continue to experience symptoms after the acute phase. Here, we report findings from a nationwide questionnaire study in Denmark including 61,002 RT-PCR confirmed SARS-CoV-2 cases and 91,878 test-negative controls aged 15-years or older. Six to twelve months after the test, the risks of 18 out of 21 symptoms were elevated among test-positives. The largest adjusted risk differences (RD) were observed for dysosmia (RD = 10.92%, 95% CI 10.68-11.21%), dysgeusia (RD = 8.68%, 95% CI 8.43-8.93%), fatigue/exhaustion (RD = 8.43%, 95%CI 8.14-8.74%), dyspnea (RD = 4.87%, 95% CI 4.65-5.09%) and reduced strength in arms/legs (RD = 4.68%, 95% CI 4.45-4.89%). During the period from the test and until completion of the questionnaire, new diagnoses of anxiety (RD = 1.15%, 95% CI 0.95-1.34%) or depression (RD = 1.00%, 95% CI 0.81-1.19%) were also more common among test-positives. Even in a population where the majority of test-positives were not hospitalized, a considerable proportion experiences symptoms up to 12 months after infection. Being female or middle-aged increases risks.

Safety of heterologous primary and booster schedules with ChAdOx1-S and BNT162b2 or mRNA-1273 vaccines: nationwide cohort study.

OBJECTIVE: To assess the risk of adverse events associated with heterologous primary (two dose) and booster (three dose) vaccine schedules for covid-19 with Oxford-AstraZeneca's ChAdOx1-S priming followed by mRNA vaccines (Pfizer-BioNTech's BNT162b2 or Moderna's mRNA-1273) as compared with homologous mRNA vaccine schedules for covid-19. DESIGN: Nationwide cohort study. SETTING: Denmark, 1 January 2021 to 26 March 2022. PARTICIPANTS: Adults aged 18-65 years who received a heterologous vaccine schedule of priming with ChAdOx1-S and one or two mRNA booster doses (with either the BNT162b2 or mRNA-1273 vaccine) were compared with adults who received a homologous BNT162b2 or mRNA-1273 vaccine schedule (ie, two dose v two dose, and three dose v three dose schedule). MAIN OUTCOME MEASURES: The incidence of hospital contacts for a range of adverse cardiovascular and haemostatic events within 28 days after the second or third vaccine dose, comparing heterologous versus homologous vaccine schedules. Secondary outcomes included additional prioritised adverse events of special interest. Poisson regression was used to estimate incidence rate ratios with adjustment for selected covariates. RESULTS: Individuals who had had a heterologous primary vaccine (n=137 495) or a homologous vaccine (n=2 688 142) were identified, in addition to those who had had a heterologous booster (n=129 770) or a homologous booster (n=2 197 213). Adjusted incidence rate ratios of adverse cardiovascular and haemostatic events within 28 days for the heterologous primary and booster vaccine schedules in comparison with the homologous mRNA vaccine schedules were 1.22 (95% confidence interval 0.79 to 1.91) and 1.00 (0.58 to 1.72) for ischaemic cardiac events, 0.74 (0.40 to 1.34) and 0.72 (0.37 to 1.42) for cerebrovascular events, 1.12 (0.13 to 9.58) and 4.74 (0.94 to 24.01) for arterial thromboembolisms, 0.79 (0.45 to 1.38) and 1.09 (0.60 to 1.98) for venous thromboembolisms, 0.84 (0.18 to 3.96) and 1.04 (0.60 to 4.55) for myocarditis or pericarditis, 0.97 (0.45 to 2.10) and 0.89 (0.21 to 3.77) for thrombocytopenia and coagulative disorders, and 1.39 (1.01 to 1.91) and 1.02 (0.70 to 1.47) for other bleeding events, respectively. No associations with any of the outcomes were found when restricting to serious adverse events defined as stay in hospital for more than 24 h. CONCLUSION: Heterologous primary and booster covid-19 vaccine schedules of ChAdOx1-S priming and mRNA booster doses as both second and third doses were not associated with increased risk of serious adverse events compared with homologous mRNA vaccine schedules. These results are reassuring but given the rarity of some of the adverse events, associations cannot be excluded.

Analysis of Thromboembolic and Thrombocytopenic Events After the AZD1222, BNT162b2, and MRNA-1273 COVID-19 Vaccines in 3 Nordic Countries.

Importance: Vaccinations are paramount to halt the COVID-19 pandemic, and safety data are essential to determine the risk-benefit ratio of each COVID-19 vaccine. Objective: To evaluate the association between the AZD1222, BNT162b2, and mRNA-1273 vaccines and subsequent thromboembolic and thrombocytopenic events. Design, Setting, and Participants: This self-controlled case series used individual-level data from national registries in Norway, Finland, and Denmark. Participants included individuals with hospital contacts because of coronary artery disease, coagulation disorders, or cerebrovascular disease between January 1, 2020, and May 16, 2021. Exposures: AZD1222, BNT162b2, or mRNA-1273 vaccine. Main Outcomes and Measure: Relative rate (RR) of hospital contacts for coronary artery disease, coagulation disorders, or cerebrovascular disease in a 28-day period following vaccination compared with the control period prior to vaccination. Results: We found 265 339 hospital contacts, of whom 112 984 [43%] were for female patients, 246 092 [93%] were for patients born in 1971 or earlier, 116 931 [44%] were for coronary artery disease, 55 445 [21%] were for coagulation disorders, and 92 963 [35%] were for cerebrovascular disease. In the 28-day period following vaccination, there was an increased rate of coronary artery disease following mRNA-1273 vaccination (RR, 1.13 [95% CI, 1.02-1.25]), but not following AZD1222 vaccination (RR, 0.92 [95% CI, 0.82-1.03]) or BNT162b2 vaccination (RR, 0.96 [95% CI, 0.92-0.99]). There was an observed increased rate of coagulation disorders following all 3 vaccines (AZD1222: RR, 2.01 [95% CI, 1.75-2.31]; BNT162b2: RR, 1.12 [95% CI, 1.07-1.19]; and mRNA-1273: RR, 1.26 [95% CI, 1.07-1.47]). There was also an observed increased rate of cerebrovascular disease following all 3 vaccines (AZD1222: RR, 1.32 [95% CI, 1.16-1.52]; BNT162b2: RR, 1.09 [95% CI, 1.05-1.13]; and mRNA-1273: RR, 1.21 [95% CI, 1.09-1.35]). For individual diseases within the main outcomes, 2 notably high rates were observed: 12.04 (95% CI, 5.37-26.99) for cerebral venous thrombosis and 4.29 (95% CI, 2.96-6.20) for thrombocytopenia, corresponding to 1.6 (95% CI, 0.6-2.6) and 4.9 (95% CI, 2.9-6.9) excess events per 100 000 doses, respectively, following AZD1222 vaccination. Conclusions and Relevance: In this self-controlled case series, there was an increased rate of hospital contacts because of coagulation disorders and cerebrovascular disease, especially for thrombocytopenia and cerebral venous thrombosis, following vaccination with AZD1222. Although increased rates of several thromboembolic and thrombocytopenic outcomes following BNT162b2 and mRNA-1273 vaccination were observed, these increases were less than the rates observed after AZD1222, and sensitivity analyses were not consistent. Confirmatory analysis on the 2 mRNA vaccines by other methods are warranted.

SARS-CoV-2 Vaccination and Myocarditis in a Nordic Cohort Study of 23 Million Residents.

Importance: Reports of myocarditis after SARS-CoV-2 messenger RNA (mRNA) vaccination have emerged. Objective: To evaluate the risks of myocarditis and pericarditis following SARS-CoV-2 vaccination by vaccine product, vaccination dose number, sex, and age. Design, Setting, and Participants: Four cohort studies were conducted according to a common protocol, and the results were combined using meta-analysis. Participants were 23 122 522 residents aged 12 years or older. They were followed up from December 27, 2020, until incident myocarditis or pericarditis, censoring, or study end (October 5, 2021). Data on SARS-CoV-2 vaccinations, hospital diagnoses of myocarditis or pericarditis, and covariates for the participants were obtained from linked nationwide health registers in Denmark, Finland, Norway, and Sweden. Exposures: The 28-day risk periods after administration date of the first and second doses of a SARS-CoV-2 vaccine, including BNT162b2, mRNA-1273, and AZD1222 or combinations thereof. A homologous schedule was defined as receiving the same vaccine type for doses 1 and 2. Main Outcomes and Measures: Incident outcome events were defined as the date of first inpatient hospital admission based on primary or secondary discharge diagnosis for myocarditis or pericarditis from December 27, 2020, onward. Secondary outcome was myocarditis or pericarditis combined from either inpatient or outpatient hospital care. Poisson regression yielded adjusted incidence rate ratios (IRRs) and excess rates with 95% CIs, comparing rates of myocarditis or pericarditis in the 28-day period following vaccination with rates among unvaccinated individuals. Results: Among 23 122 522 Nordic residents (81% vaccinated by study end; 50.2% female), 1077 incident myocarditis events and 1149 incident pericarditis events were identified. Within the 28-day period, for males and females 12 years or older combined who received a homologous schedule, the second dose was associated with higher risk of myocarditis, with adjusted IRRs of 1.75 (95% CI, 1.43-2.14) for BNT162b2 and 6.57 (95% CI, 4.64-9.28) for mRNA-1273. Among males 16 to 24 years of age, adjusted IRRs were 5.31 (95% CI, 3.68-7.68) for a second dose of BNT162b2 and 13.83 (95% CI, 8.08-23.68) for a second dose of mRNA-1273, and numbers of excess events were 5.55 (95% CI, 3.70-7.39) events per 100 000 vaccinees after the second dose of BNT162b2 and 18.39 (9.05-27.72) events per 100 000 vaccinees after the second dose of mRNA-1273. Estimates for pericarditis were similar. Conclusions and Relevance: Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273. This risk should be balanced against the benefits of protecting against severe COVID-19 disease.

A Nationwide Observational Study of Chlamydia trachomatis Infections in Denmark during the COVID-19 Pandemic.

The aim of this study was to determine whether COVID-19 restrictions had an impact on Chlamydia trachomatis infections compared with 2018 and 2019. A retrospective nationwide observational study was performed using monthly incidences of laboratory-confirmed chlamydia cases and number of tests, obtained from Danish national surveillance data. Testing rates and positivity rates were compared using Poisson and logistic regression. The first Danish COVID-19 lockdown (12 March to 14 April 2020) resulted in a reduction in the number of chlamydia tests performed (rate ratio 0.72, 95% confidence interval  0.71-0.73) and a consequent reduction in the number of laboratory-identified cases (66.5 vs 88.3 per 100,000 population during the same period in 2018 to 2019). This period was followed by a return of testing and test positivity close to the level seen in 2018 to 2019. The second Danish COVID-19 lockdown (17 December to 31 March 2021) resulted in crude incidence rates of laboratory-confirmed chlamydia infection that were similar to the crude incidence rates seen during same period in 2018 to 2019. In conclusion, the Danish COVID-19 restrictions have had negligible effects on laboratory-confirmed C. trachomatis transmission.

Assessment of Seasonality and Extremely Preterm Birth in Denmark.

Importance: Preterm birth, particularly extremely preterm birth, has been associated with substantial morbidity and mortality. Research during SARS-CoV-2-related lockdowns revealed reductions in the more severe subtypes of preterm birth in some countries, suggesting the presence of preventable risk factors, such as infectious diseases or social behavior. Seasonality may provide a similar means of assessing natural changes in the daily life of pregnant individuals that were similar to those experienced during the COVID-19 lockdown period. Objective: To evaluate the association between seasonality and extremely preterm birth. Design, Setting, and Participants: This nationwide cohort study included 1 136 143 pregnancies in Denmark with onset between January 1, 1997, and December 31, 2016, in which the fetuses survived 21 completed weeks of gestation. Pregnancies were followed up until preterm birth, fetal death, or 37 completed weeks of gestation. Data were analyzed from September 2020 to September 2021. Exposures: Season during gestation (primary exposure) and season of pregnancy onset. Main Outcomes and Measures: The main outcome of extremely preterm birth was defined as a live birth occurring between 22 weeks, 0 days' gestation and 27 weeks, 6 days' gestation. Cox regression analyses were used to estimate hazard ratios (HRs) for season during gestation and season of pregnancy onset, with adjustment for socioeconomic and demographic factors. Results: Among 662 338 pregnant individuals, the median age at pregnancy onset was 30.0 years (IQR, 6.0 years). Of 1 136 143 pregnancies, 2009 extremely preterm births (cumulative incidence, 0.18%) were identified during follow-up. Season during gestation was associated with extremely preterm birth, with cumulative incidences of 0.17% (95% CI, 0.16%-0.19%) in spring, 0.18% (95% CI, 0.17%-0.20%) in summer, 0.20% (95% CI, 0.18%-0.21%) in autumn, and 0.16% (95% CI, 0.14%-0.17%) in winter. Compared with winter, the adjusted HRs (AHRs) for the risk of extremely preterm birth were 1.11 (95% CI, 0.97-1.26) for spring, 1.15 (95% CI, 1.02-1.31) for summer, and 1.25 (95% CI, 1.10-1.42) for autumn. The number of extremely preterm births associated with the increased risk in the spring, summer, and autumn was 56.1 (95% CI, 18.2-99.7), representing 2.8% (95% CI, 0.9%-5.0%) of all extremely preterm births in the study. Season of pregnancy onset was not associated with the risk of extremely preterm birth in spring (AHR, 0.98; 95% CI, 0.95-1.01) or summer (AHR, 1.00; 95% CI, 0.96-1.03) compared with winter, but a slight increase in risk was observed in autumn (AHR, 1.05; 95% CI, 1.02-1.09) compared with winter. Conclusions and Relevance: In this large, national cohort study, seasonality was associated with 2.8% of all extremely preterm births. Season during gestation was associated with the rate of extremely preterm birth, suggesting the presence of potential risk factors associated with season that may be preventable. Further research to identify risk factors for extremely preterm birth associated with seasonality is warranted.

Association of AZD1222 and BNT162b2 COVID-19 Vaccination With Thromboembolic and Thrombocytopenic Events in Frontline Personnel : A Retrospective Cohort Study.

BACKGROUND: In March 2021, several European countries suspended the use of the AZD1222 (Oxford-AstraZeneca) COVID-19 vaccine because of thromboembolic safety concerns. Reports from Norway and Germany subsequently described patients with venous thrombosis and thrombocytopenia within 5 to 16 days of vaccination. OBJECTIVE: To evaluate the risk for outcomes related to thrombosis and thrombocytopenia after AZD1222 or BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination. DESIGN: Nationwide exploratory retrospective cohort study. SETTING: Danish linkable registers on vaccinations, hospitalizations, occupation, and other covariates. PARTICIPANTS: 355 209 Danish frontline personnel designated for priority COVID-19 vaccination followed from 27 December 2020 (the day of the first COVID-19 vaccination in Denmark) to 13 April 2021. MEASUREMENTS: Study outcomes were cerebral venous sinus thrombosis, splanchnic vein thrombosis, pulmonary embolism, deep venous thrombosis, arterial thrombosis, thrombocytopenia, and death. Cumulative incidences of study outcomes within 28 days of vaccination and unvaccinated risk time were compared using adjusted survival curves resulting in risk differences (RDs) at day 28 after vaccination. Adjustment for birth cohort, sex, calendar period, occupation, comorbid conditions, and prescription drug use was included. RESULTS: Vaccination with AZD1222 versus no vaccination was associated with a significant RD at day 28 for deep venous thrombosis (RD, 8.35 [95% CI, 0.21 to 16.49] per 100 000 vaccinations). The RDs for cerebral venous sinus thrombosis (RD, 1.68 [CI, -0.64 to 4.00] per 100 000 vaccinations) and thrombocytopenia (RD, 2.39 [CI, -1.09 to 5.87] per 100 000 vaccinations) were not significant. No adverse associations were seen for BNT162b2 vaccination. LIMITATION: No medical record review; surveillance bias. CONCLUSION: In this exploratory retrospective cohort study among frontline personnel in Denmark, receipt of the AZD1222 vaccine was associated with a small excess risk for deep venous thrombosis. Although the corresponding risks for the more rare and severe thrombotic outcomes (such as cerebral venous sinus thrombosis) were not statistically significantly increased, statistical precision was low, and clinically relevant risks could not be excluded with certainty. There was no statistically significant association of BNT162b2 vaccination with thrombotic or thrombocytopenic events. PRIMARY FUNDING SOURCE: Lundbeck Foundation.

SARS-CoV-2 vaccination and myocarditis or myopericarditis: population based cohort study.

OBJECTIVE: To investigate the association between SARS-CoV-2 vaccination and myocarditis or myopericarditis. DESIGN: Population based cohort study. SETTING: Denmark. PARTICIPANTS: 4 931 775 individuals aged 12 years or older, followed from 1 October 2020 to 5 October 2021. MAIN OUTCOME MEASURES: The primary outcome, myocarditis or myopericarditis, was defined as a combination of a hospital diagnosis of myocarditis or pericarditis, increased troponin levels, and a hospital stay lasting more than 24 hours. Follow-up time before vaccination was compared with follow-up time 0-28 days from the day of vaccination for both first and second doses, using Cox proportional hazards regression with age as an underlying timescale to estimate hazard ratios adjusted for sex, comorbidities, and other potential confounders. RESULTS: During follow-up, 269 participants developed myocarditis or myopericarditis, of whom 108 (40%) were 12-39 years old and 196 (73%) were male. Of 3 482 295 individuals vaccinated with BNT162b2 (Pfizer-BioNTech), 48 developed myocarditis or myopericarditis within 28 days from the vaccination date compared with unvaccinated individuals (adjusted hazard ratio 1.34 (95% confidence interval 0.90 to 2.00); absolute rate 1.4 per 100 000 vaccinated individuals within 28 days of vaccination (95% confidence interval 1.0 to 1.8)). Adjusted hazard ratios among female participants only and male participants only were 3.73 (1.82 to 7.65) and 0.82 (0.50 to 1.34), respectively, with corresponding absolute rates of 1.3 (0.8 to 1.9) and 1.5 (1.0 to 2.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 1.48 (0.74 to 2.98) and the absolute rate was 1.6 (1.0 to 2.6) per 100 000 vaccinated individuals within 28 days of vaccination. Among 498 814 individuals vaccinated with mRNA-1273 (Moderna), 21 developed myocarditis or myopericarditis within 28 days from vaccination date (adjusted hazard ratio 3.92 (2.30 to 6.68); absolute rate 4.2 per 100 000 vaccinated individuals within 28 days of vaccination (2.6 to 6.4)). Adjusted hazard ratios among women only and men only were 6.33 (2.11 to 18.96) and 3.22 (1.75 to 5.93), respectively, with corresponding absolute rates of 2.0 (0.7 to 4.8) and 6.3 (3.6 to 10.2) per 100 000 vaccinated individuals within 28 days of vaccination, respectively. The adjusted hazard ratio among 12-39 year olds was 5.24 (2.47 to 11.12) and the absolute rate was 5.7 (3.3 to 9.3) per 100 000 vaccinated individuals within 28 days of vaccination. CONCLUSIONS: Vaccination with mRNA-1273 was associated with a significantly increased risk of myocarditis or myopericarditis in the Danish population, primarily driven by an increased risk among individuals aged 12-39 years, while BNT162b2 vaccination was only associated with a significantly increased risk among women. However, the absolute rate of myocarditis or myopericarditis after SARS-CoV-2 mRNA vaccination was low, even in younger age groups. The benefits of SARS-CoV-2 mRNA vaccination should be taken into account when interpreting these findings. Larger multinational studies are needed to further investigate the risks of myocarditis or myopericarditis after vaccination within smaller subgroups.

Preterm birth, stillbirth and early neonatal mortality during the Danish COVID-19 lockdown.

Using provisional or opportunistic data, three nationwide studies (The Netherlands, the USA and Denmark) have identified a reduction in preterm or extremely preterm births during periods of COVID-19 restrictions. However, none of the studies accounted for perinatal deaths. To determine whether the reduction in extremely preterm births, observed in Denmark during the COVID-19 lockdown, could be the result of an increase in perinatal deaths and to assess the impact of extended COVID-19 restrictions, we performed a nationwide Danish register-based prevalence proportion study. We examined all singleton pregnancies delivered in Denmark during the COVID-19 strict lockdown calendar periods (March 12-April 14, 2015-2020, N = 31,164 births) and the extended calendar periods of COVID-19 restrictions (February 27-September 30, 2015-2020, N = 214,862 births). The extremely preterm birth rate was reduced (OR 0.27, 95% CI 0.07 to 0.86) during the strict lockdown period in 2020, while perinatal mortality was not significantly different. During the extended period of restrictions in 2020, the extremely preterm birth rate was marginally reduced, and a significant reduction in the stillbirth rate (OR 0.69, 0.50 to 0.95) was observed. No changes in early neonatal mortality rates were found.Conclusion: Stillbirth and extremely preterm birth rates were reduced in Denmark during the period of COVID-19 restrictions and lockdown, respectively, suggesting that aspects of these containment and control measures confer an element of protection. The present observational study does not allow for causal inference; however, the results support the design of studies to ascertain whether behavioural or social changes for pregnant women may improve pregnancy outcomes. What is Known: • The aetiologies of preterm birth and stillbirth are multifaceted and linked to a wide range of socio-demographic, medical, obstetric, foetal, psychosocial and environmental factors. • The COVID-19 lockdown saw a reduction in extremely preterm births in Denmark and other high-income countries. An urgent question is whether this reduction can be explained by increased perinatal mortality. What is New: • The reduction in extremely preterm births during the Danish COVID-19 lockdown was not a consequence of increased perinatal mortality, which remained unchanged during this period. • The stillbirth rate was reduced throughout the extended period of COVID-19 restrictions.

Association between inhaled corticosteroid use and COVID-19 outcomes.

BACKGROUND: Recent evidence has established a beneficial effect of systemic corticosteroids for treatment of moderate-to-severe COVID-19. OBJECTIVE: To determine if inhaled corticosteroid use is associated with COVID-19 outcomes. METHODS: In a nationwide cohort of hospitalized SARS-CoV-2 test-positive individuals in Denmark, we estimated the 30-day hazard ratio of intensive care unit (ICU) admission or death among users of inhaled corticosteroids (ICS) compared with users of bronchodilators (ß2 -agonist/muscarinic-antagonists), and non-users of ICS overall, with Cox regression adjusted for age, sex, and other confounders. We repeated these analyses among influenza test-positive patients during 2010-2018. RESULTS: Among 6267 hospitalized SARS-CoV-2 patients, 614 (9.8%) were admitted to ICU and 677 (10.8%) died within 30 days. ICS use was associated with a hazard ratio of 1.09 (95% CI [CI], 0.67 to 1.79) for ICU admission and 0.78 (95% CI, 0.56 to 1.11) for death compared with bronchodilator use. Compared with no ICS use overall, the hazard ratio of ICU admission or death was 1.17 (95% CI, 0.87-1.59) and 1.02 (95% CI, 0.78-1.32), respectively. Among 10 279 hospitalized influenza patients, of which 951 (9.2%) were admitted to ICU and 1275 (12.4%) died, the hazard ratios were 1.43 (95% CI, 0.89-2.30) and 1.11 (95% CI, 0.85-1.46) for ICU admission, and 0.80 (95% CI, 0.63-1.01) and 1.03 (95% CI, 0.87-1.22) for death compared with bronchodilator use and no ICS use overall, respectively. CONCLUSION: Our results do not support an effect of inhaled corticosteroid use on COVID-19 outcomes, however we can only rule out moderate-to-large reduced or increased risks. STUDY REGISTRATION: The study was pre-registered at encepp.eu (EUPAS35897).

Thromboembolic events in younger women exposed to Pfizer-BioNTech or Moderna COVID-19 vaccines.

Introduction: Concerns about the increased risk of blood clots associated with the VAXZEVRIA (previously named Oxford-AstraZeneca COVID-19 vaccine) and Johnson & Johnson (Janssen) COVID-19 vaccines raises the question of the thrombotic safety of other COVID-19 vaccines such as Pfizer-BioNTech or Moderna, especially in younger women, who at the early stage of the pandemic was a priority group for vaccination. Methods: Using the US-based Vaccine Adverse Event Reporting System (VAERS) and the FDA Event Reporting System (FAERS), we retrieved cases of thrombosis following vaccinations or hormonal contraceptive use in women aged ≤ 50 years. We used the reporting odds ratio (ROR) as a disproportionality measure. Results: On 19 March 2021, out of 13.6 million women aged ≤ 50 exposed to at least one dose of Pfizer-BioNTech or Moderna COVID-19 vaccines in the US, only 61 cases were reported with a total of 68 thromboembolic events (1 case per 222,951 vaccinated). None of the thromboembolic events included in our analysis were disproportionally reported for the two COVID-19 vaccines. Conclusion: Our results do support that, when compared to hormonal contraceptive use, the mRNA vaccines do not show disproportional reporting of thromboembolic events in younger women.