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Covid-19 mRNA vaccines have been shown to be associated with a short-term increased risk of myocarditis, with the highest risk observed after the second dose compared to the first. The extent of the risk associated with more distant booster doses is less clear. Here, we aimed to assess the relation between dosing interval and the risk of myocarditis, for both the two-dose primary series and the third dose (first booster). Extending our previous matched case-control study, we included 4 890 cases of myocarditis aged 12 or more and 48 900 controls up to January 31, 2022. We found that the risk of myocarditis remained elevated after the booster dose and that longer intervals between each consecutive dose (including booster doses) may decrease the occurrence of vaccine-associated myocarditis.
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IntroductionSeveral studies have reported an unexpectedly low prevalence of current smoking among hospitalized patients with Covid-19. However, these studies mostly compared observed to expected rates of smoking without direct comparison with individual controls. ObjectiveTo examine the association of nicotine-replacement therapy, as a surrogate of smoking, with hospitalization and all-cause mortality during the first wave of SARS-CoV-2 epidemic in France. MethodsWe conducted a nationwide matched "exposed/unexposed" cohort study using information from the French national health data system which covers the entire French population. We conducted two separate analyses, the first in individuals exposed to nicotine-replacement therapy without major smoking-related diseases (cancer, cardiovascular and/or respiratory diseases) and the second in those presenting these conditions. We included all individuals, aged between 18 and 75 years, who had been reimbursed at least one nicotine-replacement therapy between November 15, 2019, and February 15, 2020. For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). The three end points were a hospitalization with Covid-19, a death or an intubation in hospitalized patients with Covid-19, and all-cause mortality. We compared outcomes in individuals who were exposed to nicotine-replacement therapy with those in individuals who were not, using a multivariable Cox model with inverse probability weighting according to the propensity score. ResultsIn the first analysis, 297,070 individuals without major smoking-related diseases exposed to nicotine-replacement therapy were matched with 558,228 unexposed individuals without major smoking-related diseases. Individuals were aged on average 45.6 years (standard deviation: 12.7) and 48.8% were male. From February 15, 2020 to June 7, 2020, hospitalization with Covid-19 occurred in 647 patients (151 patients in the nicotine-replacement therapy group and 496 patients in the unexposed group). In the main multivariable analysis, nicotine-replacement therapy was associated with a decreased risk of hospitalization with Covid-19 compared with unexposed individuals (hazard ratio, 0.50; 95% CI, 0.41 to 0.61). Nicotine-replacement therapy exposure was also associated with a decreased risk of intubation or death in hospitalized individuals with Covid-19 (13 vs. 73 patients, hazard ratio, 0.31; 95% CI, 0.17 to 0.57) but with an increased risk of all-cause mortality (251 vs. 231 deaths, hazard ratio, 1.49; 95% CI, 1.24 to 1.80). In the second analysis, 128,768 individuals with major smoking-related diseases exposed to nicotine-replacement therapy were matched with 243,793 unexposed individuals. Individuals were aged on average 55.3 years (standard deviation: 11.4) and 53.3% were male. In the main multivariable analysis, nicotine-replacement therapy exposure was neither associated with risk of hospitalization with Covid-19 (240 patients in the nicotine-replacement therapy group and 398 patients in the unexposed group, hazard ratio, 1.13; 95% CI, 0.94 to 1.38) nor with risk of death or an intubation in hospitalized individuals with Covid-19 (48 vs. 61 patients, hazard ratio, 1.00; 95% CI, 0.65 to 1.54). All-cause mortality was higher in the nicotine-replacement therapy group (1040 vs. 366 deaths, hazard ratio, 3.83; 95% CI, 3.41 to 4.31). ConclusionsThis large-scale observational study suggests that smoking, measured by exposure to nicotine-replacement therapy, was associated with an increased risk of overall mortality during the first wave of SARS-CoV-2 epidemic in France, although it was associated with a lower risk of severe Covid-19 in individuals without major related-smoking diseases. Experimental and clinical studies are needed to disentangle the potential mechanisms of nicotine and/or smoking in Covid-19 risk. Whatever the nature of these associations, the global impact of smoking is harmful for health even over a short epidemic period.
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OBJECTIVES: To assess the association between prenatal exposure to monotherapy with the antiepileptic drugs (AEDs) most commonly used during pregnancy and the risk of various neurodevelopmental outcomes compared with lamotrigine. DESIGN: Nationwide population-based cohort study. SETTING: French national healthcare databases. PARTICIPANTS: Children born alive between 2011 and 2014 and prenatally exposed to AED monotherapy. PRIMARY AND SECONDARY OUTCOME MEASURES: Outcomes included neurodevelopmental disorders (NDD), defined by International Classification of Diseases, 10th Revision codes F70-F98-pervasive developmental disorders (PDD, F84) and mental retardation (MR, F70-F79) were studied separately-and visits to speech therapists. The reference group comprised children prenatally exposed to lamotrigine. Children were followed until outcome, loss to follow-up, death or 31 December 2016. We performed inverse probability of treatment weighting analyses using the propensity score, which included maternal and infant characteristics. Hazard ratios (HRs) were calculated using Cox models. RESULTS: The cohort comprised 9034 children, 2916 of which were exposed to lamotrigine, 1627 to pregabalin, 1246 to clonazepam, 991 to valproic acid (VPA), 621 to levetiracetam, 502 to carbamazepine, 477 to topiramate, 378 to gabapentin and 143 to oxcarbazepine. None of these AEDs, except VPA, was associated with an increased risk of any of the four neurodevelopmental outcomes investigated. Exposure to VPA was associated with increased risks of NDDs (HR=2.7, 95% CI (1.8 to 4.0)), PDD (HR=4.4 (2.1 to 9.3)), MR (HR=3.1 (1.5 to 6.2)) and visits to speech therapists (HR=1.5 (1.1 to 1.9)), with a dose-response relationship. CONCLUSIONS: No increased risk of any of the neurodevelopmental outcomes investigated in this study was observed with prenatal exposure to levetiracetam, pregabalin, oxcarbazepine, topiramate, gabapentin, clonazepam or carbamazepine, compared with lamotrigine. However, this study corroborates the well-known association between maternal use of VPA during pregnancy and the risk of neurodevelopmental disorders in the offspring. Longer follow-up is necessary to confirm these findings.
