Henrik Svanström

Antibiotic use and inflammatory bowel diseases in childhood

Background The composition of the intestinal microflora has been proposed as an important factor in the development of inflammatory bowel diseases (IBD). Antibiotics have the potential to alter the composition of the intestinal microflora. A study was undertaken to evaluate the potential association between use of antibiotics and IBD in childhood. Methods A nationwide cohort study was conducted of all Danish singleton children born from 1995 to 2003 (N=577 627) with individual-level information on filled antibiotic prescriptions, IBD and potential confounding variables. Using Poisson regression, rate ratios (RRs) of IBD were calculated according to antibiotic use. Antibiotic use was classified according to time since use, type, number of courses used and age at use. Results IBD was diagnosed in 117 children during 3 173 117 person-years of follow-up. The RR of IBD was 1.84 (95% CI 1.08 to 3.15) for antibiotic users compared with non-users. This association appeared to be an effect on Crohns disease (CD) alone (RR 3.41) and was strongest in the first 3 months following use (RR 4.43) and among children with ≥7 courses of antibiotics (RR 7.32). Conclusions Antibiotic use is common in childhood and its potential as an environmental risk factor for IBD warrants scrutiny. This is the first prospective study to show a strong association between antibiotic use and CD in childhood. However, as with any observational study, causality cannot be inferred from our results and confounding by indication—in particular, prescribing of antibiotics to children with intestinal symptoms of as yet undiagnosed CD—should also be considered as a possible explanation.

Autoimmune, neurological, and venous thromboembolic adverse events after immunisation of adolescent girls with quadrivalent human papillomavirus vaccine in Denmark and Sweden: cohort study

Objective To assess the risk of serious adverse events after vaccination of adolescent girls with quadrivalent human papillomavirus (qHPV) vaccine. Design Register based cohort study. Setting Denmark and Sweden, October 2006 to December 2010. Participants 997 585 girls aged 10-17, among whom 296 826 received a total of 696 420 qHPV vaccine doses. Main outcome measures Incident hospital diagnosed autoimmune, neurological, and venous thromboembolic events (53 different outcomes) up to 180 days after each qHPV vaccine dose. Only events with at least five vaccine exposed cases were considered for further assessment. Rate ratios adjusted for age, country, calendar year, and parental country of birth, education, and socioeconomic status were estimated, comparing vaccinated and unvaccinated person time. For outcomes where the rate ratio was significantly increased, we regarded three criteria as signal strengthening: analysis based on 20 or more vaccine exposed cases (reliability), rate ratio 3.0 or more (strength), and significantly increased rate ratio in country specific analyses (consistency). We additionally assessed clustering of events in time and estimated rate ratios for a risk period that started on day 181. Results Among the 53 outcomes, at least five vaccine exposed cases occurred in 29 and these were analysed further. Whereas the rate ratios for 20 of 23 autoimmune events were not significantly increased, exposure to qHPV vaccine was significantly associated with Behcet’s syndrome, Raynaud’s disease, and type 1 diabetes. Each of these three outcomes fulfilled only one of three predefined signal strengthening criteria. Furthermore, the pattern of distribution in time after vaccination was random for all three and the rate ratios for these outcomes in the period from day 181 after vaccination were similar to the rate ratios in the primary risk period. The rate ratios for five neurological events were not significantly increased and there were inverse associations with epilepsy (rate ratio 0.66, 95% confidence interval 0.54 to 0.80) and paralysis (0.56, 0.35 to 0.90). There was no association between exposure to qHPV vaccine and venous thromboembolism (0.86, 0.55 to 1.36). Conclusions This large cohort study found no evidence supporting associations between exposure to qHPV vaccine and autoimmune, neurological, and venous thromboembolic adverse events. Although associations for three autoimmune events were initially observed, on further assessment these were weak and not temporally related to vaccine exposure. Furthermore, the findings need to be interpreted considering the multiple outcomes assessed.

The incidence of narcolepsy in Europe: Before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns

BACKGROUND In August 2010 reports of a possible association between exposure to AS03 adjuvanted pandemic A(H1N1)pdm09 vaccine and occurrence of narcolepsy in children and adolescents emerged in Sweden and Finland. In response to this signal, the background rates of narcolepsy in Europe were assessed to rapidly provide information for signal verification. METHODS We used a dynamic retrospective cohort study to assess the narcolepsy diagnosis rates during the period 2000-2010 using large linked automated health care databases in six countries: Denmark, Finland, Italy, the Netherlands, Sweden and the United Kingdom. RESULTS Overall, 2608 narcolepsy cases were identified in almost 280 million person years (PY) of follow up. The pooled incidence rate was 0.93 (95% CI: 0. 90-0.97) per 100,000 PY. There were peaks between 15 and 30 year of age (women>men) and around 60 years of age. In the age group 5-19 years olds rates were increased after the start of pandemic vaccination compared to the period before the start of campaigns, with rate ratios (RR) of 1.9 (95% CI: 1.1-3.1) in Denmark, 6.4 (95% CI: 4.2-9.7) in Finland and 7.5 (95% CI: 5.2-10.7) in Sweden. Cases verification in the Netherlands had a significant effect on the pattern of incidence over time. CONCLUSIONS The results of this incidence study provided useful information for signal verification on a population level. The safety signal of increased narcolepsy diagnoses following the start of the pandemic vaccination campaign as observed in Sweden and Finland could be observed with this approach. An increase in narcolepsy diagnoses was not observed in other countries, where vaccination coverage was low in the affected age group, or did not follow influenza A(H1N1)pdm09 vaccination. Patient level analyses in these countries are being conducted to verify the signal in more detail.

Use of Azithromycin and Death from Cardiovascular Causes

BACKGROUND Azithromycin use is associated with an increased risk of death from cardiovascular causes among patients at high baseline risk. Whether azithromycin confers a similar risk in the unselected general population is unknown. METHODS We conducted a nationwide historical cohort study involving Danish adults (18 to 64 years of age), linking registry data on filled prescriptions, causes of death, and patient characteristics for the period from 1997 through 2010. We estimated rate ratios for death from cardiovascular causes, comparing 1,102,050 episodes of azithromycin use with no use of antibiotic agents (matched in a 1:1 ratio according to propensity score, for a total of 2,204,100 episodes) and comparing 1,102,419 episodes of azithromycin use with 7,364,292 episodes of penicillin V use (an antibiotic with similar indications; analysis was conducted with adjustment for propensity score). RESULTS The risk of death from cardiovascular causes was significantly increased with current use of azithromycin (defined as a 5-day treatment episode), as compared with no use of antibiotics (rate ratio, 2.85; 95% confidence interval [CI], 1.13 to 7.24). The analysis relative to an antibiotic comparator included 17 deaths from cardiovascular causes during current azithromycin use (crude rate, 1.1 per 1000 person-years) and 146 during current penicillin V use (crude rate, 1.5 per 1000 person-years). With adjustment for propensity scores, current azithromycin use was not associated with an increased risk of cardiovascular death, as compared with penicillin V (rate ratio, 0.93; 95% CI, 0.56 to 1.55). The adjusted absolute risk difference for current use of azithromycin, as compared with penicillin V, was -1 cardiovascular death (95% CI, -9 to 11) per 1 million treatment episodes. CONCLUSIONS Azithromycin use was not associated with an increased risk of death from cardiovascular causes in a general population of young and middle-aged adults. (Funded by the Danish Medical Research Council.).

Risk of Adverse Fetal Outcomes Following Administration of a Pandemic Influenza A(H1N1) Vaccine During Pregnancy

CONTEXT Assessment of the fetal safety of vaccination against influenza A(H1N1)pdm09 in pregnancy has been limited. OBJECTIVE To investigate whether exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was associated with increased risk of adverse fetal outcomes. DESIGN, SETTING, AND PARTICIPANTS Registry-based cohort study based on all liveborn singleton infants in Denmark, delivered between November 2, 2009, and September 30, 2010. In propensity score-matched analyses, we estimated prevalence odds ratios (PORs) of adverse fetal outcomes, comparing infants exposed and unexposed to an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy. MAIN OUTCOME MEASURES Major birth defects, preterm birth, and small size for gestational age. RESULTS From a cohort of 53,432 infants (6989 [13.1%] exposed to the influenza A[H1N1]pdm09 vaccine during pregnancy [345 in the first trimester and 6644 in the second or third trimester]), 660 (330 exposed) were included in propensity score-matched analyses of adverse fetal outcomes associated with first-trimester exposure. For analysis of small size for gestational age after second- or third-trimester exposure, 13,284 (6642 exposed) were included; for analyses of preterm birth, 12,909 (6543 exposed) were included. A major birth defect was diagnosed in 18 of 330 infants (5.5%) exposed to the vaccine in the first trimester, compared with 15 of 330 unexposed infants (4.5%) (POR, 1.21; 95% CI, 0.60-2.45). Preterm birth occurred in 31 of 330 infants (9.4%) exposed in the first trimester, compared with 24 of 330 unexposed infants (7.3%) (POR, 1.32; 95% CI, 0.76-2.31), and in 302 of 6543 infants (4.6%) with second- or third-trimester exposure, compared with 295 of 6366 unexposed infants (4.6%) (POR, 1.00; 95% CI, 0.84-1.17). Small size for gestational age was observed in 25 of 330 infants (7.6%) with first-trimester exposure compared with 31 of 330 unexposed infants (9.4%) (POR, 0.79; 95% CI, 0.46-1.37), and in 641 of 6642 infants (9.7%) with second- or third-trimester exposure, compared with 657 of 6642 unexposed infants (9.9%) (POR, 0.97; 95% CI, 0.87-1.09). CONCLUSIONS In this Danish cohort, exposure to an adjuvanted influenza A(H1N1)pdm09 vaccine during pregnancy was not associated with a significantly increased risk of major birth defects, preterm birth, or fetal growth restriction.

Use of Azathioprine and the Risk of Cancer in Inflammatory Bowel Disease

Increased risks of lymphoma and skin cancer associated with thiopurine use among patients with inflammatory bowel disease have been shown, but data on the overall cancer risk are limited. We conducted a historical cohort study of 45,986 patients with inflammatory bowel disease (of whom, 5,197 (11%) used azathioprine) in Denmark from 1997 to 2008. We linked registry data on filled drug prescriptions, cancer diagnoses, and covariates and compared rates of overall incident cancer and cancer subgroups between users and nonusers of azathioprine, adjusting for propensity scores. During a median 7.9 (interquartile range: 3.5-12.0) person-years of follow-up, 2,596 incident cases of cancer were detected. Azathioprine use was associated with an increased risk of overall cancer (rate ratio = 1.41, 95% confidence interval: 1.15, 1.74), whereas former use of azathioprine (rate ratio = 1.02, 95% confidence interval: 0.83, 1.25) or increasing cumulative received doses (increase in rate ratio per 365 additional defined daily doses = 1.06, 95% confidence interval: 0.89, 1.27) were not. In subgroup analyses, azathioprine use was associated with increased risk of lymphoid tissue cancer (rate ratio = 2.40, 95% confidence interval: 1.13, 5.11) and urinary tract cancer (rate ratio = 2.84, 95% confidence interval: 1.24, 6.51). In conclusion, azathioprine use was associated with an increased risk of overall cancer in patients with inflammatory bowel disease, although these data cannot establish causality.

Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark

Objective To investigate whether an adjuvanted pandemic A/H1N1 2009 influenza vaccine in pregnancy was associated with an increased risk of fetal death. Design Nationwide register based cohort study. Setting Denmark. Participants All clinically recognised singleton pregnancies that ended between November 2009 and September 2010. Individual level data on exposure to an inactivated AS03 pandemic A/H1N1 2009 influenza vaccine (Pandemrix) and potential confounders were linked to the study cohort using a unique person identifier. Main outcome measures The primary outcome measure was risk of fetal death (spontaneous abortion and stillbirth combined) in H1N1 vaccinated compared with unvaccinated pregnancies, adjusting for propensity scores. Secondary outcome measures were spontaneous abortion (between seven and 22 weeks’ gestation) and stillbirth (after 22 completed weeks’ gestation). Results The cohort comprised 54 585 pregnancies; 7062 (12.9%) women were vaccinated against pandemic A/H1N1 2009 influenza during pregnancy. Overall, 1818 fetal deaths occurred (1678 spontaneous abortions and 140 stillbirths). Exposure to the H1N1 vaccine was not associated with an increased risk of fetal death (adjusted hazard ratio 0.79, 95% confidence interval 0.53 to 1.16), or the secondary outcomes of spontaneous abortion (1.11, 0.71 to 1.73) and stillbirth (0.44, 0.20 to 0.94). Estimates for fetal death were similar in pregnant women with (0.82, 0.44 to 1.53) and without comorbidities (0.77, 0.47 to 1.25). Conclusion This large cohort study found no evidence of an increased risk of fetal death associated with exposure to an adjuvanted pandemic A/H1N1 2009 influenza vaccine during pregnancy.

Quadrivalent HPV Vaccination and Risk of Multiple Sclerosis and Other Demyelinating Diseases of the Central Nervous System

IMPORTANCE Case reports have suggested a link between human papillomavirus (HPV) vaccination and development of multiple sclerosis and other demyelinating diseases. OBJECTIVE To investigate if quadrivalent HPV (qHPV) vaccination is associated with an increased risk of multiple sclerosis and other demyelinating diseases. DESIGN, SETTING, AND PARTICIPANTS Using nationwide registers we identified a cohort of all females aged 10 years to 44 years in Denmark and Sweden, followed up from 2006 to 2013, information on qHPV vaccination, and data on incident diagnoses of multiple sclerosis and other demyelinating diseases. The primary analysis used a cohort design including vaccinated and unvaccinated study participants. A secondary analysis used a self-controlled case-series design including only cases. Both analyses used a 2-year risk period following vaccination. EXPOSURES Information on qHPV vaccination was obtained through the national vaccination and prescription registers. MAIN OUTCOMES AND MEASURES The primary outcomes were multiple sclerosis and a composite end point of other demyelinating diseases. Incidence rate ratios were estimated using Poisson regression, comparing rates of events in the 2-year risk periods following vaccination and in unvaccinated time periods. RESULTS The study included 3,983,824 females, among whom 789,082 received a total of 1,927,581 qHPV vaccine doses. During follow-up, 4322 multiple sclerosis cases and 3300 cases of other demyelinating diseases were identified, of which 73 and 90, respectively, occurred within the risk period. In the cohort analysis, there was no increased risk of multiple sclerosis (crude incidence rates, 6.12 events/100,000 person-years [95% CI, 4.86-7.69] and 21.54 events/100,000 person-years [95% CI, 20.90-22.20] for the vaccinated and unvaccinated periods; adjusted rate ratio, 0.90 [95% CI, 0.70-1.15]) or other demyelinating diseases (crude incidence rates, 7.54 events/100,000 person-years [95% CI, 6.13-9.27] and 16.14 events/100,000 person-years [95% CI, 15.58-16.71]; adjusted rate ratio, 1.00 [95% CI, 0.80-1.26]) associated with qHPV vaccination. Similarly, no increased risk was found using the self-controlled case-series design (multiple sclerosis: incidence ratio, 1.05 [95% CI, 0.79-1.38]; other demyelinating diseases: incidence ratio, 1.14 [95% CI, 0.88-1.47]). CONCLUSIONS AND RELEVANCE In this study with nationwide coverage of 2 Scandinavian countries, qHPV vaccination was not associated with the development of multiple sclerosis or other demyelinating diseases. These findings do not support concerns about a causal relationship between qHPV vaccination and demyelinating diseases.

Association Between Tumor Necrosis Factor-α Antagonists and Risk of Cancer in Patients With Inflammatory Bowel Disease

IMPORTANCE A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data to evaluate these effects. OBJECTIVE To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer. DESIGN, SETTING, AND PARTICIPANTS Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56,146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry. MAIN OUTCOMES AND MEASURES Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF-α antagonist users and nonusers, estimated using Poisson regression adjusted for age, calendar year, disease duration, propensity scores, and use of other IBD medications. RESULTS During 489,433 person-years of follow-up (median, 9.3 years [interquartile range, 4.2-14.0]), 81 of 4553 patients exposed to TNF-α antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8-6.0]) and 3465 of 51,593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85-1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-α antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67-1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77-1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54-1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88-2.03]) and in analyses according to the number of TNF-α antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71-1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55-1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90-1.85]). No site-specific cancers were in significant excess in fully adjusted models. CONCLUSIONS AND RELEVANCE In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.

Use of Calcium Channel Blockers and Parkinson’s Disease

Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinsons disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinsons disease (1998-2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinsons disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinsons disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinsons disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinsons disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinsons disease, particularly in older patients, and with reduced mortality among patients with Parkinsons disease.