Mediating pathways between neighborhood disadvantage and cardiovascular risk: Quasi-experimental evidence from a Danish refugee dispersal policy.

Research has documented that neighborhood disadvantage is associated with increased cardiovascular disease risk, but it is unclear which mechanistic pathways mediate this association across the life course. Leveraging a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998 and using 30 years of follow-up data from population and health registers, we assessed whether and how individual-level poverty, unstable employment, and poor mental health mediate the relation between neighborhood disadvantage and the risk of hypertension, hyperlipidemia, and type 2 diabetes among Danish refugees (N= 40,811). Linear probability models using the discrete time-survival framework showed that neighborhood disadvantage was associated with increased risk of hypertension (0.05 percentage points [pp] per year [95%CI -0.00, 0.10]); hyperlipidemia (0.03 pp per year [95%CI -0.01, 0.07]), and diabetes (0.01 pp per year (95%CI -0.02, 0.03)). The Baron-Kenny product-of-coefficients method for counterfactual mediation analysis indicated that cumulative income mediated 6%-28% of the disadvantage effect on these outcomes. We find limited evidence of mediation by unstable employment and poor mental health. This study informs our theoretical understanding of the pathways linking neighborhood disadvantage with cardiovascular disease risk and identifies income security as a promising point of intervention in future research.

The association of neighborhood socioeconomic characteristics with cardiovascular health: A quasi-experimental study of refugees to Denmark.

Neighborhood socioeconomic disadvantage is associated with cardiovascular health, although it is unclear which specific aspects of neighborhoods matter most. We leveraged a natural experiment in which refugees to Denmark were quasi-randomly assigned to neighborhoods across the country during 1986-1998, creating variation in exposure to various aspects of neighborhood disadvantage. The cohort was followed through December 2018. Exposures included neighborhood-level family income, educational attainment, unemployment, and welfare transfers measured in the first neighborhood after arrival to Denmark. Outcomes included cardiovascular risk factors (hyperlipidemia, hypertension, diabetes and anxiety/depression) and cardiovascular disease (acute myocardial infarction and ischemic heart disease). Neighborhood-level income and education were most consistently associated with cardiovascular risk factors, whereas welfare transfers were most consistently associated with cardiovascular disease. Addressing these specific aspects of neighborhood disadvantage could therefore lower the risk of poor cardiovascular health among refugees. Future research is warranted to examine if results are generalizable to other immigrant groups, countries or time periods.

Neighborhood disadvantage and the risk of dementia and mortality among refugees to Denmark: A quasi-experimental study.

Objectives: Neighborhood disadvantage may increase the risk of adverse health outcomes among older refugees. Yet few studies rigorously estimate the effects of place-based factors on later-life health, particularly dementia and mortality. Evidence about refugees is especially sparse. Methods: This study leveraged a natural experiment in the form of a Danish policy (1986-1998) that dispersed refugees quasi-randomly across neighborhoods upon arrival. We used longitudinal registers allowing 30 years of follow-up among refugees aged 40+ years upon arrival in Denmark (N = 9,854). Cox models assessed the association between neighborhood disadvantage and risk of dementia and mortality. We examined heterogeneous effects by sex, age, and family size. We also examined associations among non-refugee immigrants and native-born Danes. Results: Neighborhood disadvantage was not associated with dementia in any group. One unit increase in neighborhood disadvantage index (ranges -8 to 5.7) was associated with greater mortality risk among non-refugee immigrants (HR 1.06, 95%CI: 1.02, 1.10) and native-born Danes (HR 1.11, 95%CI: 1.06, 1.17). In contrast, neighborhood disadvantage was associated with lower mortality risk among refugees (HR 0.96, 95%CI: 0.93, 0.99). Neighborhood disadvantage remained negatively associated with mortality risk in subgroups: refugees who are female (on moderate-disadvantage compared to low-disadvantage), aged 60+, and who arrived with families. Discussion: While neighborhood disadvantage was associated with lower mortality risk among refugees, it was associated with greater mortality risk among non-refugee immigrants and native-born Danes, perhaps due to confounding in the latter groups or different place-based experiences by immigration status. Future research is warranted to explain the reasons for contrasting findings.

Neighbourhood socioeconomic disadvantage and psychiatric disorders among refugees: a population-based, quasi-experimental study in Denmark.

PURPOSE: Refugees are vulnerable to psychiatric disorders because of risk factors linked to migration. Limited evidence exist on the impact of the neighbourhood in which refugee resettle. We examined whether resettling in a socioeconomically disadvantaged neighbourhood increased refugees' risk of psychiatric disorders. METHODS: This register-based cohort study included 42,067 adults aged 18 years and older who came to Denmark as refugees during 1986-1998. Resettlement policies in those years assigned refugees in a quasi-random fashion to neighbourhoods across the country. A neighbourhood disadvantage index was constructed using neighbourhood-level data on income, education, unemployment, and welfare receipt. Main outcomes were psychiatric diagnoses and psychiatric medication usage ascertained from nationwide patient and prescription drug registers, with up to 30-year follow-up. Associations of neighbourhood disadvantage with post-migration risk of psychiatric disorders were examined using Cox proportional hazards and linear probability models adjusted for individual, family, and municipality characteristics. RESULTS: The cumulative risk of psychiatric diagnoses and medication was 13.7% and 46.1%, respectively. Refugees' risk of psychiatric diagnoses and psychiatric medication usage was higher among individuals assigned to high-disadvantage compared with low-disadvantage neighbourhoods in analyses including fixed effects for assigned municipality (psychiatric diagnoses: hazard ratio (HR) = 1.14, 95% CI 1.04, 1.25; psychiatric medication: HR = 1.05, 95% CI 1.00, 1.11). Consistent results were found using linear probability models. Results for diagnostic categories and subclasses of medications suggested that the associations were driven by neurotic and stress-related disorders and use of anxiolytic medications. CONCLUSION: Resettlement in highly disadvantaged neighbourhoods was associated with an increase in refugees' risk of psychiatric disorders, suggesting that targeted placement of newly arrived refugees could benefit refugee mental health. The results contribute quasi-experimental evidence to support links between neighbourhood characteristics and health.

Corrigendum: Risk of reoperation due to surgical site infection in 74,771 hip fracture patients: a Danish nationwide cohort study.

Corrigendum of Acta Orthop 2022; 93: 760-766. doi: https://doi.org/10.2340/17453674.2022.4580.

Risk of reoperation due to surgical site infection in 74,771 hip fracture patients: a Danish nationwide cohort study.

BACKGROUND AND PURPOSE: Surgical site infection (SSI) after hip fracture surgery is a feared condition. We examined the trend in incidence of reoperation due to SSI up to 1 year following hip fracture surgery from 2005 to 2016 and risk factors of SSI by age, sex, comorbidity, type of fracture, and surgery. PATIENTS AND METHODS: We conducted a population-based, nationwide cohort study using data from the Danish Multidisciplinary Hip Fracture Register (DMHFR). We included 74,771 patients aged 65 and up who underwent surgery from 2005 to 2016 for all types of hip fracture. We calculated net risk of reoperation using Kaplan­Meier method, and, with Cox regression, adjusted hazard ratios (HRs) with a 95% confidence interval (CI) for reoperation due to SSI. RESULTS: Overall, the 1-year net risk of reoperation due to SSI was 1.6%. The HR was higher for patients undergoing total/hemiarthroplasty surgery versus internal fixation (HR = 1.5; 95%CI 1.3­1.8) and lower for patients with per-/subtrochanteric fracture versus femoral neck fracture (HR = 0.6; CI 0.6­0.7). The risk of reoperation due to SSI decreased over time; HR was 0.7 (CI 0.5­0.8) for 2015­2016 compared with 2005­2006. Risk of reoperation decreased with increasing age; the HR was 0.8 (CI 0.7­1.0) in the more than 85-year-olds compared with 65­74-year-old patients. Charlson Comorbidity Index of ≥ 3 was associated with a higher risk of reoperation due to SSI, HR was 1.3 (CI 1.1­1.6). INTERPRETATION: The net risk of reoperations due to SSI in our study was lower than previously assumed. We identified several risk factors for increased risk of reoperation due to SSI, most noticeably treatment with arthroplasty vs. internal fixation, as well as younger age, high comorbidity burden, and femoral neck fracture diagnosis.

Risk of Psychiatric Disorders Among Refugee Children and Adolescents Living in Disadvantaged Neighborhoods.

Importance: Refugee children and adolescents are at increased risk of mental health difficulties, but little is known about how the characteristics of the neighborhood in which they resettle may affect vulnerability and resilience. Objective: To test whether neighborhood socioeconomic disadvantage is associated with risk of psychiatric disorders among refugee children and adolescents and examine whether the association differs by sex, age at arrival, and family structure. Design, Setting, and Participants: This quasi-experimental register-based cohort study included refugees in Denmark aged 0 to 16 years at the time of resettlement from 1986 to 1998. A refugee dispersal policy implemented during those years assigned housing to refugee families in neighborhoods with varying degrees of socioeconomic disadvantage in a quasi-random (ie, arbitrary) manner conditional on refugee characteristics observed by placement officers. Cox proportional hazard models were used to examine the association between neighborhood disadvantage and risk of psychiatric disorders, adjusting for relevant baseline covariates. Exposures: A neighborhood disadvantage index combining information on levels of income, education, unemployment, and welfare assistance in the refugees' initial quasi-randomly assigned neighborhood. Main Outcomes and Measures: First-time inpatient or outpatient diagnosis of a psychiatric disorder before age 30 years. Results: Median (IQR) baseline age in the sample of 18 709 refugee children and adolescents was 7.9 (4.7-11.7) years; 8781 participants (46.9%) were female and 9928 (53.1%) were male. During a median (IQR) follow-up period of 16.1 (10.2-20.8) years, 1448 refugees (7.7%) were diagnosed with a psychiatric disorder (incidence rate, 51.2 per 10 000 person-years). An increase of 1 SD in neighborhood disadvantage was associated with an 11% increase in the hazard of a psychiatric disorders (hazard ratio [HR], 1.11; 95% CI, 1.03-1.21). This association did not differ between male and female individuals, refugees who arrived at different ages, or those from single- vs dual-parent households. In secondary analyses using prescribed psychiatric medication as the outcome, a similar association with neighborhood disadvantage was found (HR, 1.08; 95% CI, 1.03-1.14). Conclusions and Relevance: In this cohort study, neighborhood disadvantage was associated with an increase in risk of psychiatric disorders. The results suggest that placement of refugee families in advantaged neighborhoods and efforts to enhance the neighborhood context in disadvantaged areas may improve mental health among refugee children and adolescents.

Early-Life Exposure to Antibiotics and Risk for Crohn's Disease: A Nationwide Danish Birth Cohort Study.

BACKGROUND: Early-life antibiotic use can alter the intestinal flora and modify the risk of developing Crohn disease (CD), but rigorous epidemiological evidence is limited, with inconsistent results. METHODS: We identified all children born in Denmark from 1995 to 2009 and followed them from birth until death, emigration, a diagnosis of CD, or January 1, 2013. Using Cox regression, we assessed the association between antibiotic exposure in the first year of life and subsequent risk for CD, adjusting for sex, degree of urbanization, birth order, birth year, route of delivery, gestational age, smoking during pregnancy, intake of nonsteroidal anti-inflammatory drugs in the first year of life, and family history of CD. RESULTS: During a median 9.5 years (9.3 million total person-years), CD was diagnosed in 208 of 979,039 children. Antibiotic use in the first year of life was associated with a higher risk of CD (adjusted hazard ratio, 1.4; 95% confidence interval [CI], 1.1-1.8), with the highest risk with ≥6 courses of antibiotics (adjusted hazard ratio, 4.1; 95% CI, 2.0-8.5). A family history of CD did not modify these risk associations. The cumulative risk of CD at the 11th birthday for children exposed to antibiotics in their first year of life was 0.16‰ (95% CI, 0.11‰-0.22‰) compared to 0.11‰ (95% CI, 0.08‰-0.15‰) for children unexposed to antibiotics in their first year of life. CONCLUSIONS: Antibiotic use in the first year of life is associated with a modestly increased risk for CD, although the absolute risk is very low.

Mortality and revision risk after femoral neck fracture: comparison of internal fixation for undisplaced fracture with arthroplasty for displaced fracture: a population-based study from Danish National Registries.

Background and purpose - Hemiarthroplasty has lower reoperation frequency and better mobilization compared with internal fixation (IF) in patients with undisplaced femoral neck fractures (FNF), which might translate into lower mortality. In this population-based cohort study we compare the risk of mortality and reoperation in undisplaced FNF treated with IF and displaced FNF treated with arthroplasty in patients older than 70 years old. We assume that, per se, there is no difference in mortality risk between patients with a displaced and an undisplaced FNF.Patients and methods - Hip fracture patients were identified in the Danish Multidisciplinary Hip Fracture Registry during 2005-2015. Data on medication, comorbidities, reoperation, and mortality were retrieved from other Danish medical databases. IF and arthroplasty patients were compared with regards to mortality and reoperation up to 5 years postoperatively. We calculated hazard ratios (HR) with 95% confidence intervals (CI) adjusting for relevant confounders.Results - We included 19,260 FNF treated with arthroplasty and 10,337 FNF with IF. There was an increased risk of mortality for arthroplasty within 30 days, HR 1.3 (95% CI 1.3-1.4), compared with IF but not after 1 and 5 years. Arthroplasty patients had adjusted HRs for reoperation of 0.8 (0.8-0.9) within 1 year, 0.8 (0.7-0.9) within 2 years, and 0.8 (0.8-0.9) within 5 years postoperatively compared with IF.Interpretation - Patients treated for a displaced FNF with arthroplasty had a higher risk of 30-day mortality compared with patients who had an undisplaced FNF treated with IF. It has to be considered that there were baseline differences in the groups but there was no difference in mortality risk up to 5 years post-surgery. Concerning reoperation, patients with a displaced FNF treated with arthroplasty had a lower risk of reoperation compared with IF for undisplaced FNF.

Prognostic impact of elevated lactate levels on mortality in critically ill patients with and without preadmission metformin treatment: a Danish registry-based cohort study.

BACKGROUND: Lactate is a robust prognostic marker for the outcome of critically ill patients. Several small studies reported that metformin users have higher lactate levels at ICU admission without a concomitant increase in mortality. However, this has not been investigated in a larger cohort. We aimed to determine whether the association between lactate levels around ICU admission and mortality is different in metformin users compared to metformin nonusers. METHODS: This cohort study included patients admitted to ICUs in northern Denmark between January 2010 and August 2017 with any circulating lactate measured around ICU admission, which was defined as 12 h before until 6 h after admission. The association between the mean of the lactate levels measured during this period and 30-day mortality was determined for metformin users and nonusers by modelling restricted cubic splines obtained from a Cox regression model. RESULTS: Of 37,293 included patients, 3183 (9%) used metformin. The median (interquartile range) lactate level was 1.8 (1.2-3.2) in metformin users and 1.6 (1.0-2.7) mmol/L in metformin nonusers. Lactate levels were strongly associated with mortality for both metformin users and nonusers. However, the association of lactate with mortality was different for metformin users, with a lower mortality rate in metformin users than in nonusers when admitted with similar lactate levels. This was observed over the whole range of lactate levels, and consequently, the relation of lactate with mortality was shifted rightwards for metformin users. CONCLUSION: In this large observational cohort of critically ill patients, early lactate levels were strongly associated with mortality. Irrespective of the degree of hyperlactataemia, similar lactate levels were associated with a lower mortality rate in metformin users compared with metformin nonusers. Therefore, lactate levels around ICU admission should be interpreted according to metformin use.

Risk of adverse birth outcomes after maternal varenicline use: A population-based observational study in Denmark and Sweden.

PURPOSE: To examine risks of adverse birth outcomes in women exposed to varenicline during pregnancy. METHODS: Population-based cohort study including live-born and stillborn infants from 1 May 2007 to 31 December 2012. Data from health and administrative registries in Denmark and Sweden, two Nordic countries with universal health care and routine registration of major life and health events. Infants were allocated to three cohorts on the basis of their in utero exposure: the exposed cohort consisting of infants whose mothers were dispensed varenicline during pregnancy; the unexposed cohort comprised infants unexposed to varenicline, but exposed to maternal smoking in utero; and the reference cohort of infants unexposed to varenicline and maternal smoking in utero. The primary outcome was major congenital malformations diagnosed from birth to the first year of life. Secondary outcomes included stillbirth, fetal growth restriction (measured as small for gestational age), preterm delivery, preterm premature rupture of membranes, and sudden infant death syndrome. We estimated the prevalence of the primary outcome and secondary outcomes in the exposed, unexposed, and reference cohorts. Prevalence odds ratios with 95% confidence intervals (CIs) were computed using logistic regression with propensity score adjustment to control for potential confounders. RESULTS: The combined cohort included 885 185 infants. Of these, 335 infants were exposed, 78 412 were unexposed, and the remaining 806 438 comprised the reference cohort. Major congenital malformations were detected among 3.6% of exposed infants, 4.3% of unexposed infants, and 4.2% of infants in the reference cohort. The propensity score-adjusted prevalence odds ratio for major congenital malformations was 0.80 (95% CI, 0.45-1.42) for exposed vs unexposed infants. All analyses of primary and secondary outcomes comparing exposed with unexposed infants yielded odds ratio estimates below or close to unity. Use of varenicline during pregnancy does not appear to increase the risk of major congenital malformations or other adverse birth outcomes.

Influence of Acetylsalicylic Acid Use on Risk and Outcome of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Study.

OBJECTIVE: To investigate the influence of acetylsalicylic acid (ASA) use on risk and outcome of community-acquired Staphylococcus aureus bacteremia (CA-SAB). METHOD: We used population-based medical databases to identify all patients diagnosed in northern Denmark with first-time CA-SAB and matched population controls from 2000-2011. Categories for ASA users included current users (new or long-term users), former users, and nonusers. The analyses were adjusted for comorbidities, comedication use, and socioeconomic indicators. RESULTS: We identified 2638 patients with first-time CA-SAB and 26 379 matched population controls. Compared with nonusers, the adjusted odds ratio (aOR) for CA-SAB was 1.00 (95% confidence interval [CI], 0.88-1.13) for current users, 1.00 (95% CI, 0.86-1.16) for former users, 2.04 (95% CI, 1.42-2.94) for new users, and 0.95 (95% CI, 0.84-1.09) for long-term users. Thirty-day cumulative mortality was 28.0% among current users compared with 21.6% among nonusers, yielding an adjusted hazard rate ratio (aHRR) of 1.02 (95% CI, 0.84-1.25). Compared with nonusers, the aHRR was 1.10 (95% CI, 0.87-1.40) for former users, 0.60 (95% CI, 0.29-1.21) for new users, and 1.06 (95% CI, 0.87-1.31) for long-term users. We observed no difference in the risk or outcome of CA-SAB with increasing ASA dose or by presence of diseases commonly treated with ASA. CONCLUSIONS: Use of ASA did not seem to influence the risk or outcome of CA-SAB. The apparent increased risk among new users may relate to residual confounding from the circumstances underlying ASA treatment initiation. Our finding of no association remained robust with increasing ASA dose and across multiple patient subsets.

Feasibility of salivary DNA collection in a population-based case-control study: a pilot study of pediatric Crohn's disease.

BACKGROUND: Epidemiologic studies combining exposure and outcome data with the collection of biosamples are needed to study gene-environment interactions that might contribute to the etiology of complex diseases such as pediatric Crohn's disease (CD). Nationwide registries, including those in Denmark and other Scandinavian countries, provide efficient and reliable sources of data for epidemiological studies evaluating the environmental determinants of disease. We performed a pilot study to test the feasibility of collecting salivary DNA to augment registry data in established cases of pediatric CD and randomly selected, population-based controls. SUBJECTS AND METHODS: Cases of CD born after 1995 and residing in the central region of Denmark were identified through the Danish National Patient Registry and confirmed by using standard diagnostic criteria. Age- and gender-matched controls were selected at random through the civil registration system. Cases and controls were contacted by mail and telephone and invited to submit a saliva sample. DNA was extracted and genotyped for six CD-associated single-nucleotide polymorphisms (SNPs). RESULTS: A total of 53 cases of pediatric CD were invited, and 40 contributed a saliva sample (75% response rate). A total of 126 controls were invited, and 54 contributed a saliva sample (44% response rate). As expected, demographic characteristics did not differ between cases and controls. DNA was successfully isolated from 93 of 94 samples. Genotyping was performed with only 2% undetermined genotypes. For five of six SNPs known to be associated with CD, risk allele frequencies were higher in cases than controls. CONCLUSION: This pilot study strongly supports the feasibility of augmenting traditional epidemiological data from Danish population-based registries with the de novo collection of genetic information from population-based cases and controls. This will facilitate rigorous studies of gene-environment interactions in complex chronic conditions such as CD.

Open versus laparoscopic rectal cancer resection and risk of subsequent incisional hernia repair and paracolostomy hernia repair: a nationwide population-based cohort study.

OBJECTIVE: To investigate the risk of incisional hernia repair (IHR) and paracolostomy hernia repair (PHR) following open and laparoscopic rectal cancer resection with curative intent. BACKGROUND: Laparoscopic rectal cancer resection has been implemented to varying degrees around the world. IHR and PHR following open and laparoscopic rectal cancer resection have only been sparingly evaluated. METHODS: Patients who underwent rectal cancer resection were identified in the Danish Colorectal Cancer Group's database. To identify IHR and PHR following rectal cancer resection, we linked data to the Danish Ventral Hernia Database. The absolute risk of IHR and PHR was estimated as cumulative incidence proportions, treating death as competing risk. We used Cox proportional hazard regression analysis with multivariable adjustment to compute hazard ratios (HRs) comparing open and laparoscopic approach. RESULTS: The 5-year risk of IHR was 4.1% among patients undergoing open resection (n = 3090) and 3.2% among those undergoing laparoscopic resection (n = 3099), corresponding to a risk difference of 0.9% (95% CI 0.0-2.0, P = 0.057). Laparoscopic rectal resection was not associated with lower risk of IHR (adjusted HR 0.94, 95% CI 0.67-1.31, P = 0.709). A total of 2577 patients had a colostomy at rectal cancer resection and the 5-year risk of PHR was 2.1% after open surgery compared with 6.7% after laparoscopic surgery, corresponding to a risk difference of -4.6% (95% CI -6.4 to -2.7, P < 0.001). Laparoscopic surgery was associated with increased risk of PHR (adjusted HR 2.56, 95% CI 1.53-4.29, P < 0.001). CONCLUSION: We observed no association between surgical approach of rectal cancer resection and subsequent IHR. Laparoscopic surgery was associated with increased risk of PHR.

Statin Use and Risk of Community-Acquired Staphylococcus aureus Bacteremia: A Population-Based Case-Control Study.

OBJECTIVE: To ascertain whether persons treated with statins experience a decreased risk of community-acquired Staphylococcus aureus bacteremia (CA-SAB) as compared with nonusers. PATIENTS AND METHODS: Using population-based medical registries, we conducted a case-control study including all adults with first-time CA-SAB and population controls matched on age, sex, and residence in Northern Denmark from January 1, 2000, through December 31, 2011. Statin users were categorized as current users (new or long-term use), former users, and nonusers. We used conditional logistic regression to compute odds ratios (ORs) for CA-SAB according to statin exposure, overall and stratified by intensity (<20, 20-39, ≥40 mg/d) and duration of use (<365, 365-1094, ≥1095 days). RESULTS: We identified 2638 patients with first-time CA-SAB and 26,379 matched population controls. Compared with nonusers, current statin users experienced markedly decreased risk of CA-SAB (adjusted OR, 0.73; 95% CI, 0.63-0.84). The adjusted OR was 0.96 (95% CI, 0.60-1.51) for new users, 0.71 (95% CI, 0.62-0.82) for long-term users, and 1.12 (95% CI, 0.94-1.32) for former users as compared with nonusers. The CA-SAB risk decreased with increasing intensity of statin use; thus, compared with nonusers, the adjusted OR was 0.84 (95% CI, 0.68-1.04) for current users with daily dosages of less than 20 mg/d, 0.71 (95% CI, 0.58-0.87) for 20 to 39 mg/d, and 0.63 (95% CI, 0.49-0.81) for 40 mg/d or more. Conversely, we observed no differences in the risk of CA-SAB with successive increases in the duration of statin use. CONCLUSION: Statin use was associated with a decreased risk of CA-SAB, particularly in long-term users.

Use of glucocorticoids during pregnancy and risk of attention-deficit/hyperactivity disorder in offspring: a nationwide Danish cohort study.

OBJECTIVE: Prenatal exposure to excess endogenous glucocorticoid (GC) has been linked to attention-deficit/hyperactivity disorder (ADHD). We investigated whether prenatal exposure to exogenous GC is associated with ADHD. DESIGN: Nationwide cohort study. SETTING: A cohort of 875 996 singletons born alive between 1996 and 2009 in Denmark. Data were obtained from national registries. EXPOSURES: We identified children exposed prenatally to GCs, children unexposed prenatally and born to maternal former users, and children unexposed and born to maternal never users. MAIN OUTCOME MEASURES: We compared ADHD risk in children prenatally exposed to GCs and in children of former GC users with risk in unexposed children of never users. We computed cumulative incidence at 10 years of age and adjusted HRs (aHRs). In addition, we compared exposed children with unexposed siblings in a sibling design. RESULTS: We identified 875 996 children, among whom 5319 were prenatally exposed to systemic GCs and 36 780 to local/inhaled GCs. Cumulative incidences of ADHD at 10 years of age were 2.65% in prenatally exposed children and 2.03% in unexposed children of never users. At the general population level, prenatal exposure was associated with ADHD compared with unexposed, with aHR of 1.43(95% CI 1.24 to 1.65) for systemic exposure and 1.23 (95% CI 1.15 to 1.31) for local/inhaled exposure. However, our former user analysis (aHR of 1.25 (95% CI 1.20 to 1.29)) and sibling design (aHR of 1.03 (95% CI 0.87 to 1.20)) indicated that these findings were due to confounding. CONCLUSION: This study provides no evidence of a causal association between prenatal exposure to GCs and risk of ADHD.

Trends in Antibiotic Use by Birth Season and Birth Year.

OBJECTIVES: We examined 2 birth cohort effects on antibiotic prescribing during the first year of life (henceforth, infancy) in Denmark: (1) the birth season effect on timing and overall occurrence of antibiotic prescribing, and (2) the birth year effect amid emerging nationwide pneumococcal vaccination programs and changing prescribing guidelines. METHODS: We linked data for all live births in Denmark from 2004 to 2012 (N = 561 729) across the National Health Service Prescription Database, Medical Birth Registry, and Civil Registration System. Across birth season and birth year cohorts, we estimated 1-year risk, rate, and burden of redeemed antibiotic prescriptions during infancy. We used interrupted time series methods to assess prescribing trends across birth year cohorts. Graphical displays of all birth cohort effect data are included. RESULTS: The 1-year risk of having at least 1 redeemed antibiotic prescription during infancy was 39.5% (99% confidence interval [CI]: 39.3% to 39.6%). The hazard of a first prescription increased with age throughout infancy and varied by season; subsequently, Kaplan-Meier-derived risk functions varied by birth season cohort. After rollout of a first vaccination program and new antibiotic prescribing guidelines, 1-year risk decreased by 4.4% over 14 months (99% CI: 3.4% to 5.5%); it decreased again after rollout of a second vaccination program by 6.9% over 3 years (99% CI: 4.4% to 9.3%). CONCLUSIONS: In Denmark, birth season and birth year cohort effects influenced timing and risk of antibiotic prescribing during infancy. Future studies of antibiotic stewardship, effectiveness, and safety in children should consider these cohort effects, which may render some children inherently more susceptible than others to downstream antibiotic effects.

Use of azithromycin and risk of ventricular arrhythmia.

BACKGROUND: There are conflicting findings from observational studies of the arrhythrogenic potential of azithromycin. Our aim was to quantify the association between azithromycin use and the risk of ventricular arrhythmia. METHODS: We conducted a nested case-control study within a cohort of new antibiotic users identified from a network of 7 population-based health care databases in Denmark, Germany, Italy, the Netherlands and the United Kingdom for the period 1997-2010. Up to 100 controls per case were selected and matched by age, sex and database. Recency of antibiotic use and type of drug (azithromycin was the exposure of interest) at the index date (occurrence of ventricular arrhythmia) were identified. We estimated the odds of ventricular arrhythmia associated with current azithromycin use relative to current amoxicillin use or nonuse of antibiotics (≥ 365 d without antibiotic exposure) using conditional logistic regression, adjusting for confounders. RESULTS: We identified 14 040 688 new antibiotic users who met the inclusion criteria. Ventricular arrhythmia developed in 12 874, of whom 30 were current azithromycin users. The mean age of the cases and controls was 63 years, and two-thirds were male. In the pooled data analyses across databases, azithromycin use was associated with an increased risk of ventricular arrhythmia relative to nonuse of antibiotics (adjusted odds ratio [OR] 1.97, 95% confidence interval [CI] 1.35-2.86). This increased risk disappeared when current amoxicillin use was the comparator (adjusted OR 0.90, 95% CI 0.48-1.71). Database-specific estimates and meta-analysis confirmed results from the pooled data analysis. INTERPRETATION: Current azithromycin use was associated with an increased risk of ventricular arrhythmia when compared with nonuse of antibiotics, but not when compared with current amoxicillin use. The decreased risk with an active comparator suggests significant confounding by indication.