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1.  Algorithm linking patients and general practices in Denmark using the Danish National Health Service Register 
Clinical Epidemiology  2016;8:273-283.
The patient list system in Denmark assigns virtually all residents to a general practice. Nevertheless, historical information on this link between patient and general practice is not readily available for research purposes.
To develop, implement, and evaluate the performance of an algorithm linking individual patients to their general practice by using information from the Danish National Health Service Register and the Danish Civil Registration System.
Materials and methods
The National Health Service Register contains information on all services provided by general practitioners from 1990 and onward. On the basis of these data and information on migration history and death obtained from the Civil Registration System, we developed an algorithm that allocated patients to a general practice on a monthly basis. We evaluated the performance of the algorithm between 2002 and 2007. During this time period, we had access to information on the link between patients and general practices. Agreement was assessed by the proportion of months for which the algorithm allocated patients to the correct general practice. We also assessed the proportion of all patients in the patient list system for which the algorithm was able to suggest an allocation.
The overall agreement between algorithm and patient lists was 98.6%. We found slightly higher agreement for women (98.8%) than for men (98.4%) and lower agreement in the age group 18–34 years (97.1%) compared to all other age groups (≥98.6%). The algorithm had assigned 83% of all patients in the patient list system after 1 year of follow-up, 91% after 2 years of follow-up, and peaked at 94% during the fourth year.
We developed an algorithm that enables valid and nearly complete linkage between patients and general practices. The algorithm performs better in subgroups of patients with high health care needs. The algorithm constitutes a valuable tool for primary health care research.
PMCID: PMC4984827  PMID: 27563255
general practice; medical record linkage; patient list; primary care; registers
2.  Ten-Year Mortality after a Breast Cancer Diagnosis in Women with Severe Mental Illness: A Danish Population-Based Cohort Study 
PLoS ONE  2016;11(7):e0158013.
Breast cancer is the leading cause of cancer death in women worldwide. Nevertheless, it is unknown whether higher mortality after breast cancer contributes to the life-expectancy gap of 15 years in women with severe mental illness (SMI).
We estimated all-cause mortality rate ratios (MRRs) of women with SMI, women with breast cancer and women with both disorders compared to women with neither disorder using data from nationwide registers in Denmark for 1980–2012.
The cohort included 2.7 million women, hereof 31,421 women with SMI (12,852 deaths), 104,342 with breast cancer (52,732 deaths), and 1,106 with SMI and breast cancer (656 deaths). Compared to women with neither disorder, the mortality was 118% higher for women with SMI (MRR: 2.18, 95% confidence interval (CI): 2.14–2.22), 144% higher for women with breast cancer (MRR: 2.44, 95% CI: 2.42–2.47) and 327% higher for women with SMI and breast cancer (MRR: 4.27, 95% CI: 3.98–4.57). Among women with both disorders, 15% of deaths could be attributed to interaction. In a sub-cohort of women with breast cancer, the ten-year all-cause-mortality was 59% higher after taking tumor stage into account (MRR: 1.59, 95% CI: 1.47–1.72) for women with versus without SMI.
The mortality among women with SMI and breast cancer was markedly increased. More information is needed to determine which factors might explain this excess mortality, such as differences between women with and without SMI in access to diagnostics, provision of care for breast cancer or physical comorbidity, health-seeking-behavior, and adherence to treatment.
PMCID: PMC4963132  PMID: 27462907
3.  Impact of Depression and Diabetes on Risk of Dementia In a National Population-Based Cohort 
JAMA psychiatry  2015;72(6):612-619.
Although depression and type 2 diabetes may independently increase dementia risk, no studies have examined whether the risk of dementia among people with both is higher than the sum of each individually.
To examine risk of all-cause dementia among persons with depression, diabetes or both compared to those with neither.
A population-based cohort study of 2,454,532 adults, including 477,133 (19.4%) with depression, 223,174 (9.1%) with diabetes and 95,691 (3.9%) with both.
All dementia-free Danish citizens ≥50 years old between January 1, 2007 through 2013.
Main outcome measure
Dementia was ascertained by physician diagnosis from the Danish National Patient Register, the Danish Psychiatric Central Register (DPCR), and/or prescription of a cholinesterase inhibitor or memantine from the Danish National Prescription Registry (DNPR). Depression was ascertained by psychiatrist diagnosis from the DPCR or antidepressant prescription from the DNPR. Diabetes was identified using the Danish National Diabetes Register. The risk of all-cause dementia associated with diabetes, depression or both was estimated using Cox proportional hazards regression models that adjusted for potential confounding factors such as demographics and potential intermediates such as medical comorbidity.
During 13,834,645 million person-years of follow-up, 59,663 (2.4%) developed dementia of whom 6,466 (10.8%) had diabetes, 15,729 (26.4%) had depression and 4,022 (6.7%) had both. The adjusted hazard ratio of developing all-cause dementia was 1.83 (95% confidence interval: 1.80, 1.87) for persons with depression, 1.20 (95% CI: 1.17, 1.23) for persons with diabetes, and 2.17 (95% CI: 2.10, 2.24) for those with both as compared to those with neither. The excess risk of all-cause dementia observed for individuals with comorbid depression and diabetes surpassed the summed risk associated with the two individually, especially for younger persons. The corresponding Attributable Proportion due to the interaction of comorbid depression and diabetes was 0.25 (95% CI = 0.13, 0.36; P<0.001) for those under 65 years old and 0.06 (95% CI = 0.02, 0.10; P=0.001) for those over 65.
Depression and diabetes were independently associated with greater dementia risk and the combined association of the two disorders with risk of all-cause dementia was stronger than additive.
PMCID: PMC4666533  PMID: 25875310
5.  Long-term risk of atrial fibrillation after the death of a partner 
Open Heart  2016;3(1):e000367.
Severe psychological stress is generally associated with an increased risk of acute cardiovascular diseases, such as myocardial infarction, but it remains unknown whether it also applies to atrial fibrillation. We conducted a population-based case–control study using nationwide Danish health registers to examine the risk of atrial fibrillation after the death of a partner.
From 1995 through 2014, we identified 88 612 cases with a hospital diagnosis of atrial fibrillation and 886 120 age-matched and sex-matched controls based on risk-set sampling. The conditional logistic regression model was used to calculate adjusted ORs of atrial fibrillation with 95% CIs.
Partner bereavement was experienced by 17 478 cases and 168 940 controls and was associated with a transiently higher risk of atrial fibrillation; the risk was highest 8–14 days after the loss (1.90; 95% CI 1.34 to 2.69), after which it gradually declined. One year after the loss, the risk was almost the same as in the non-bereaved population. Overall, the OR of atrial fibrillation within 30 days after bereavement was 1.41 (95% CI 1.17 to 1.70), but it tended to be higher in persons below the age of 60 years (2.34; 95% CI 1.02 to 5.40) and in persons whose partner had a low predicted mortality 1 month before the death, that is, ≤5 points on the age-adjusted Charlson Comorbidity Index (1.57; 95% CI 1.13 to 2.17).
The severely stressful life event of losing a partner was followed by a transiently increased risk of atrial fibrillation lasting for 1 year, especially for the least predicted losses.
PMCID: PMC4823543  PMID: 27099762
6.  Hospital-based herpes zoster diagnoses in Denmark: rate, patient characteristics, and all-cause mortality 
Herpes zoster (HZ) may result in severe complications requiring hospital treatment, particularly in patients with comorbidity. Nevertheless, data on HZ from nationwide population-based hospital registries are sparse.
We conducted a cohort study describing first-time hospital-based (inpatient, outpatient, and emergency room) HZ diagnoses in the Danish National Patient Registry, 1994–2012. We computed the diagnosis rate; prevalence of demographic characteristics, comorbidities, and complications; length of hospital stay; and standardized mortality ratios (SMRs) using the Danish population as reference. We classified comorbidity using the Charlson Comorbidity Index (CCI) scoring system and categorized patients in groups of no (score 0), moderate (score 1), severe (score 2), and very severe comorbidity (score ≥3). In addition, we computed the prevalence of certain conditions associated with immune dysregulation (stem cell or bone marrow transplantation, solid organ transplantation, HIV infection, primary immunodeficiency, any cancer, and autoimmune diseases).
The diagnosis rate increased almost exponentially from 6 to 91.9 per 100,000 person-years between age 50 and ≥90 years. The age-standardized rate was stable throughout the study period. The median length of hospital stay was 4 days (interquartile range: 1–8 days) for inpatients with HZ as the main reason for admission. According to the CCI, 44.3 % of patients had no comorbidity, 17.3 % moderate comorbidity, 17.4 % severe comorbidity, and 21.0 % very severe comorbidity. Comorbidities involving immune dysregulation, such as malignant (21 %) and autoimmune diseases (17 %), were particularly prevalent. Thirty percent had neurological, ophthalmic, or other complications. HZ was associated with increased all-cause mortality overall (SMR 1.8, 95 % CI: 1.7–1.8), but not in analyses restricted to patients without comorbidity (SMR 1.0, 95 % CI: 0.9–1.0).
This study provides estimates of the epidemiology of hospital-based (severe) HZ. The diagnosis rate increased substantially with age. Complications and comorbidities were prevalent, likely resulting in increased mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s12879-016-1369-6) contains supplementary material, which is available to authorized users.
PMCID: PMC4773995  PMID: 26932311
Complications; Epidemiology; Herpes zoster; Hospitalization; Outpatient clinics; Hospital
7.  Early Life Bereavement and Schizophrenia 
Medicine  2016;95(3):e2434.
Supplemental Digital Content is available in the text
We aimed to examine whether early life bereavement, as indicator of severe stress, was associated with an increased risk of schizophrenia later in life.
Based on population registers, we established a cohort of all children born in Denmark (N = 1 686 416) and Sweden (N = 2 563 659) from 1973 to 1997. Children were categorized as exposed if they lost a first-degree relative during the first 18 years of life. Outcome is the first diagnosis of schizophrenia as either inpatient or outpatient. Log-linear Poisson regression models were used to estimate incidence rate ratios (IRRs).
A total of 188,850 children (4.6%) experienced death of a first-degree relative from birth to 18 years of age. Compared with unexposed children, those exposed had overall a 39% higher risk of schizophrenia (= 1.39, 95% CI [confidence interval]: 1.32–1.47). The IRR was particularly high if the family member committed suicide (aIRR = 2.11, 95% CI: 1.90–2.34) or died due to an injury or accident (aIRR = 1.44, 95% CI: 1.27–1.63). The IRR of schizophrenia decreased with increasing child's age at bereavement (P < 0.0001). Children who experienced >1 death during the first 18 years of life (aIRR = 1.79, 95% CI: 1.46–2.19) had a higher risk than those with a single death (aIRR = 1.37, 95% CI: 1.30–1.45).
The study suggested that exposure to death of a first-degree relative before 18 years was associated with an increased risk of schizophrenia in later life. The complex mechanisms behind these associations remain to be elucidated.
PMCID: PMC4998249  PMID: 26817875
8.  Bodily distress syndrome: A new diagnosis for functional disorders in primary care? 
BMC Family Practice  2015;16:180.
Conceptualisation and classification of functional disorders appear highly inconsistent in the health-care system, particularly in primary care. Numerous terms and overlapping diagnostic criteria are prevalent of which many are considered stigmatising by general practitioners and patients. The lack of a clear concept challenges the general practitioner’s decision-making when a diagnosis or a treatment approach must be selected for a patient with a functional disorder. This calls for improvements of the diagnostic categories. Intense debate has risen in connection with the release of the fifth version of the ‘Diagnostic and Statistical Manual of Mental Disorders’ and the current revision of the ‘International Statistical Classification of Diseases and Related Health Problems’. We aim to discuss a new evidence based diagnostic proposal, bodily distress syndrome, which holds the potential to change our current approach to functional disorders in primary care. A special focus will be directed towards the validity and utility criteria recommended for diagnostic categorisation.
A growing body of evidence suggests that the numerous diagnoses for functional disorders listed in the current classifications belong to one family of closely related disorders. We name the underlying phenomenon ‘bodily distress’; it manifests as patterns of multiple and disturbing bodily sensations. Bodily distress syndrome is a diagnostic category with specific criteria covering this illness phenomenon. The category has been explored through empirical studies, which in combination provide a sound basis for determining a symptom profile, the diagnostic stability and the boundaries of the condition. However, as bodily distress syndrome embraces only the most common symptom patterns, patients with few but impairing symptoms are not captured. Furthermore, the current lack of treatment options may also influence the acceptance of the proposed diagnosis.
Bodily distress syndrome is a diagnostic category with notable validity according to empirical studies. Nevertheless, knowledge is sparse on the utility in primary care. Future intervention studies should investigate the translation of bodily distress syndrome into clinical practice. A particular focus should be directed towards the acceptability among general practitioners and patients. Most importantly, it should be investigated whether the new category may provide the basis for better treatment and improved clinical outcome.
PMCID: PMC4681035  PMID: 26669977
Bodily distress syndrome; Functional disorders; General practice; Diagnosis; Diagnostic utility; Diagnostic validity; Medically unexplained symptoms
9.  Fetal growth and preterm birth in children exposed to maternal or paternal rheumatoid arthritis. A nationwide cohort study 
To assess indicators of fetal growth and risk of preterm birth in children of parents with rheumatoid arthritis (RA).
Through linkage of Danish national registries we identified all children born in Denmark between 1977 and 2008. We used general linear regression models to estimate mean differences in indicators of fetal growth among children having a parent with RA compared to unexposed children. Odds ratios of preterm birth were calculated by a logistic regression model.
Of the 1,917,723 children included, a total of 13,556 children were exposed to maternal RA or maternal preclinical RA. Children exposed to maternal RA (2,101) had approximately similar length, head and abdominal circumference at birth, compared with children of mothers without RA. Birth weight was 87 gram lower (−87.04 g; 95% CI, −111.23; −62.84) and placenta weight was 14 gram lower (−13.45 g; 95% CI, −21.46; −5.43). Rather similar results were found in children exposed to maternal preclinical RA (11,455). Compared with unexposed children a higher risk of preterm birth was found in children exposed to maternal RA and maternal preclinical RA respectively (OR, 1.48; 95% CI,1.20;1.84 and OR, 1.32; 95% CI,1.07;1.64). No associations were found with paternal RA.
Children exposed to either maternal RA or maternal preclinical RA are more often born preterm. However, indicators of fetal growth measured at birth were only slightly lower than in unexposed children.
PMCID: PMC4245456  PMID: 25393524
Rheumatoid arthritis; birth weight; birth length; indicators of fetal growth; preterm birth; pregnancy outcome
10.  Depression and risk of hospitalisations and rehospitalisations for ambulatory care-sensitive conditions in Denmark: a population-based cohort study 
BMJ Open  2015;5(12):e009878.
Hospitalisations for ambulatory care-sensitive conditions (ACSCs), a group of chronic and acute illnesses considered not to require inpatient treatment if timely and appropriate ambulatory care is received, and early rehospitalisations are common and costly. We sought to determine whether individuals with depression are at increased risk of hospitalisations for ACSCs, and rehospitalisation for the same or another ACSC, within 30 days.
National, population-based cohort study.
5 049 353 individuals ≥18 years of age between 1 January 2005 and 31 December 2013.
Depression was ascertained via psychiatrist diagnoses in the Danish Psychiatric Central Register or antidepressant prescription redemption from the Danish National Prescription Registry. Hospitalisations for ACSCs and rehospitalisations within 30 days were identified using the Danish National Patient Register.
Overall, individuals with depression were 2.35 times more likely to be hospitalised for an ACSC (95% CI 2.32 to 2.37) versus those without depression after adjusting for age, sex and calendar period, and 1.45 times more likely after adjusting for socioeconomic factors, comorbidities and primary care utilisation (95% CI 1.43 to 1.46). After adjusting for ACSC-predisposing comorbidity, depression was associated with significantly greater risk of hospitalisations for all chronic (eg, angina, diabetes complications, congestive heart failure exacerbation) and acute ACSCs (eg, pneumonia) compared to those without depression. Compared to those without depression, persons with depression were 1.21 times more likely to be rehospitalised within 30 days for the same ACSC (95% CI 1.18 to 1.24) and 1.19 times more likely to be rehospitalised within 30 days for a different ACSC (95% CI 1.15 to 1.23).
Individuals with depression are at increased risk of hospitalisations for ACSCs, and once discharged are at elevated risk of rehospitalisations within 30 days for ACSCs.
PMCID: PMC4679902  PMID: 26634401
11.  Cancer Mortality in People Treated with Antidepressants before Cancer Diagnosis: A Population Based Cohort Study 
PLoS ONE  2015;10(9):e0138134.
Depression is common after a cancer diagnosis and is associated with an increased mortality, but it is unclear whether depression occurring before the cancer diagnosis affects cancer mortality. We aimed to study cancer mortality of people treated with antidepressants before cancer diagnosis.
Methods and Findings
We conducted a population based cohort study of all adults diagnosed with cancer between January 2003 and December 2010 in Denmark (N = 201,662). We obtained information on cancer from the Danish Cancer Registry, on the day of death from the Danish Civil Registry, and on redeemed antidepressants from the Danish National Prescription Registry. Current users of antidepressants were defined as those who redeemed the latest prescription of antidepressant 0–4 months before cancer diagnosis (irrespective of earlier prescriptions), and former users as those who redeemed the latest prescription five or more months before cancer diagnosis. We estimated an all-cause one-year mortality rate ratio (MRR) and a conditional five-year MRR for patients who survived the first year after cancer diagnosis and confidence interval (CI) using a Cox proportional hazards regression model. Overall, 33,111 (16.4%) patients redeemed at least one antidepressant prescription in the three years before cancer diagnosis of whom 21,851 (10.8%) were current users at the time of cancer diagnosis. Current antidepressant users had a 32% higher one-year mortality (MRR = 1.32, 95% CI: 1.29–1.35) and a 22% higher conditional five-year mortality (MRR = 1.22, 95% CI: 1.17–1.26) if patients survived the first year after the cancer diagnosis than patients not redeeming antidepressants. The one-year mortality was particularly high for patients who initiated antidepressant treatment within four months before cancer diagnosis (MRR = 1.54, 95% CI: 1.47–1.61). Former users had no increased cancer mortality.
Initiation of antidepressive treatment prior to cancer diagnosis is common and is associated with an increased mortality.
PMCID: PMC4569483  PMID: 26367120
12.  Apgar-score in children prenatally exposed to antiepileptic drugs: a population-based cohort study 
BMJ Open  2015;5(9):e007425.
It is unknown if prenatal exposure to antiepileptic drugs (AEDs) increases the risk of low Apgar score in offspring.
Population-based study using health registers in Denmark.
We identified all 677 021 singletons born in Denmark from 1997 to 2008 and linked the Apgar score from the Medical Birth Register with information on the women's prescriptions for AEDs during pregnancy from the Danish Register of Medicinal Product Statistics. We used the Danish National Hospital Registry to identify mothers diagnosed with epilepsy before birth of the child. Results were adjusted for smoking and maternal age.
Among 2906 children exposed to AEDs, 55 (1.9%) were born with an Apgar score ≤7 as compared with 8797 (1.3%) children among 674 115 pregnancies unexposed to AEDs (adjusted relative risk (aRR)=1.41 (95% CI 1.07 to 1.85). When analyses were restricted to the 2215 children born of mothers with epilepsy, the aRR of having a low Apgar score associated with AED exposure was 1.34 (95% CI 0.90 to 2.01) When assessing individual AEDs, we found increased, unadjusted RR for exposure to carbamazepine (RR=1.86 (95% CI 1.01 to 3.42)), valproic acid (RR=1.85 (95% CI 1.04 to 3.30)) and topiramate (RR=2.97 (95% CI 1.26 to 7.01)) when compared to unexposed children.
Prenatal exposure to AEDs was associated with increased risk of being born with a low Apgar score, but the absolute risk of a low Apgar score was <2%. Risk associated with individual AEDs indicate that the increased risk is not a class effect, but that there may be particularly high risks of a low Apgar score associated with certain AEDs.
PMCID: PMC4567672  PMID: 26359281
13.  Patient characteristics and frequency of bodily distress syndrome in primary care: a cross-sectional study 
The British Journal of General Practice  2015;65(638):e617-e623.
Bodily distress syndrome (BDS) is a newly proposed diagnosis of medically unexplained symptoms, which is based on empirical research in primary care.
To estimate the frequency of BDS in primary care and describe the characteristics of patients with BDS.
Design and setting
A cross-sectional study of primary care patients in urban and rural areas of Central Denmark Region.
Data were obtained from GP one-page registration forms, patient questionnaires (including a checklist for BDS), and national registers.
A total of 1356 primary care patients were included, of whom 230 patients (17.0%, 95% confidence intervals [CI] = 15.0 to 19.1) fulfilled the BDS criteria. BDS was more common among primary care patients aged 41–65 years (odds ratio [OR] = 1.9, 95% CI = 1.3 to 3.0) and was equally frequent among males and females (female sex, OR 0.9, 95% CI = 0.6 to 1.3). Patients with BDS were characterised by poor health-related quality of life (HRQOL) on the 12-item Short-Form Health Survey, that is, physical component summary scores <40 (OR 20.5, 95% CI = 12.9 to 32.4) and mental component summary scores <40 (OR 3.5, 95% CI = 2.2 to 5.6). Furthermore, patients with BDS were more likely to have high scores on the Symptom Checklist for anxiety (OR 2.2, 95% CI = 1.4 to 3.4) and depression (OR 5.1, 95% CI = 3.3 to 7.9), but regression analyses showed that mental morbidity did not account for the poor HRQOL.
BDS is common among primary care patients, and patients with BDS have a higher probability of poor HRQOL and mental health problems.
PMCID: PMC4540402  PMID: 26324499
cross-sectional analysis; general practice; signs and symptoms; somatoform disorders
14.  Healthcare Contacts after Myocardial Infarction According to Mental Health and Socioeconomic Position: A Population-Based Cohort Study 
PLoS ONE  2015;10(7):e0134557.
To examine the long-term use of healthcare contacts to general practice (GP) and hospital after a first-time myocardial infarction (MI) according to mental health and socioeconomic position.
Population-based cohort study of all patients discharged with first-time MI in the Central Denmark Region in 2009 (n=908) using questionnaires and nationwide registers. We estimated adjusted incidence rates and incidence rate ratios (IRR) for GP and hospital contacts according to depressive and anxiety symptoms, educational level and cohabitation status.
During the 24-month period after the MI, patients with anxiety symptoms had 24% more GP contacts (adjusted IRR 1.24, 95% confidence interval (CI) 1.12–1.36) than patients with no anxiety symptoms. In contrast, patients with depressive symptoms (1.05, 0.94–1.16) and with short and medium education (<10 years: 0.96, 0.84–1.08; 10–12 years: 0.91, 0.80–1.03) and patients living alone (0.95, 0.87–1.04) had the same number of GP contacts as their counterparts (patients with no depressive symptoms, with long education [>12 years] and patients living with a partner). During the first 6 months after the MI, patients living alone had 13% fewer hospital contacts (0.87, 0.77–0.99), patients with short education had 16% fewer hospital contacts (<10 years: 0.84, 0.72–0.98) and patients with anxiety symptoms had 27% fewer hospital contacts (0.73, 0.62–0.86) than their counterparts. In contrast, patients with depressive symptoms (0.92, 0.77–1.10) and medium education (10–12 years: 1.05, 0.91–1.22) had the same number of hospital contacts as their counterparts.
This study indicates that patients with depressive symptoms, short and medium education and patients living alone have a lower long-term use of healthcare contacts following MI than patients without these risk factors. Patients with depressive symptoms and low socioeconomic position would be expected to have a higher need of healthcare after MI as they have a poorer prognosis.
PMCID: PMC4520472  PMID: 26225864
15.  Prenatal Valproate Exposure and Risk of Autism Spectrum Disorders and Childhood Autism 
JAMA  2013;309(16):1696-1703.
Valproate is used for the treatment of epilepsy and other neuropsychological disorders and may be the only treatment option for women of childbearing potential. However, prenatal exposure to valproate may increase the risk of autism.
To determine whether prenatal exposure to valproate is associated with an increased risk of autism in offspring.
Design, Setting, and Participants
Population-based study of all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). We analyzed the risks associated with all autism spectrum disorders as well as childhood autism. Data were analyzed by Cox regression adjusting for potential confounders (maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity). Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.
Main Outcomes and Measures
Absolute risk (cumulative incidence) and the hazard ratio (HR) of autism spectrum disorder and childhood autism in children after exposure to valproate in pregnancy.
Of 655 615 children born from 1996 through 2006, 5437 were identified with autism spectrum disorder, including 2067 with childhood autism. The mean age of the children at end of follow-up was 8.84 years (range, 4-14; median, 8.85). The estimated absolute risk after 14 years of follow-up was 1.53% (95% CI, 1.47%- 1.58%) for autism spectrum disorder and 0.48% (95% CI, 0.46%-0.51%) for childhood autism. Overall, the 508 children exposed to valproate had an absolute risk of 4.42% (95% CI, 2.59%-7.46%) for autism spectrum disorder (adjusted HR, 2.9 [95% CI, 1.7-4.9]) and an absolute risk of 2.50% (95% CI, 1.30%-4.81%) for childhood autism (adjusted HR, 5.2 [95% CI, 2.7-10.0]). When restricting the cohort to the 6584 children born to women with epilepsy, the absolute risk of autism spectrum disorder among 432 children exposed to valproate was 4.15% (95% CI, 2.20%-7.81%) (adjusted HR, 1.7 [95% CI, 0.9-3.2]), and the absolute risk of childhood autism was 2.95% (95% CI, 1.42%-6.11%) (adjusted HR, 2.9 [95% CI, 1.4-6.0]) vs 2.44% (95% CI, 1.88%-3.16%) for autism spectrum disorder and 1.02% (95% CI, 0.70%-1.49%) for childhood autism among 6152 children not exposed to valproate.
Conclusions and Relevance
Maternal use of valproate during pregnancy was associated with a significantly increased risk of autism spectrum disorder and childhood autism in the offspring, even after adjusting for maternal epilepsy. For women of childbearing potential who use antiepileptic medications, these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.
PMCID: PMC4511955  PMID: 23613074
16.  Risk of Fetal Death after Treatment with Antipsychotic Medications during Pregnancy 
PLoS ONE  2015;10(7):e0132280.
Antipsychotic medications are increasingly used during pregnancy. Nevertheless, fetal risks are still not fully studied. It is currently unclear whether the antipsychotic treatment might induce a higher risk of fetal death. We aimed to determine if use of antipsychotic medication during pregnancy is associated with an increased risk of spontaneous abortion or stillbirth.
In a historical cohort study, we identified all clinically recognized pregnancies registered in the nationwide Danish registries from 1997 to 2008 (N = 1,005,319). Exposure was defined as any prescription of antipsychotic medications redeemed by the pregnant women during the exposure window, and recorded in the Danish National Prescription Register. Outcome was defined as any spontaneous abortion or stillbirth recorded in the Danish National Hospital Register and the Danish Medical Birth Register respectively.
Women exposed to antipsychotic medications during pregnancy had a 34% higher risk of spontaneous abortion (adjusted relative risk = 1.34; 95% confidence interval = 1.22; 1.46) compared to unexposed women, but a similar risk compared to women exposed prior to (but not during) pregnancy (adjusted relative risk = 1.04; 95% confidence interval = 0.93; 1.17). The risk of spontaneous abortion was not increased in exposed pregnancies when compared to unexposed pregnancies in the same women (adjusted hazard ratio = 1.11; 95% CI = 0.94; 1.31). A twofold higher risk of stillbirth was found in women exposed to antipsychotic medications compared with unexposed women (relative risk = 2.27; 95% confidence interval = 1.45; 3.55) and compared with women exposed only prior to pregnancy (relative risk = 2.06; 95% confidence interval = 1.01; 4.19).
The increased risk of spontaneous abortion found in women treated with antipsychotic medications during pregnancy is most likely due to confounding factors. The risk of stillbirth was twofold higher in pregnancies exposed to antipsychotic medication during pregnancy. Treatment with antipsychotic medications during pregnancy requires careful consideration.
PMCID: PMC4498617  PMID: 26162087
17.  Common variants associated with general and MMR vaccine-related febrile seizures 
Nature genetics  2014;46(12):1274-1282.
Febrile seizures represent a recognized serious adverse event following measles, mumps, and rubella (MMR) vaccination. We conducted a series of genome-wide association scans comparing children with MMR-related febrile seizures, children with febrile seizures unrelated to vaccination, and controls with no history of febrile seizures. Two loci were distinctly associated with MMR-related febrile seizures, harboring the interferon-stimulated gene IFI44L (rs273259; P = 5.9×10−12 vs. controls; P =1.2×10−9 vs. MMR-unrelated febrile seizures) and the measles virus receptor CD46 (rs1318653; P = 9.6×10−11 vs. controls; P = 1.6×10−9 vs. MMR-unrelated febrile seizures). Furthermore, four loci were associated with febrile seizures in general implicating the sodium channel genes SCN1A (rs6432860; P = 2.2×10−16) and SCN2A (rs3769955; P = 3.1×10−10), a TMEM16 family gene (TMEM16C; rs114444506; P = 3.7×10−20), and a region associated with magnesium levels (12q21.33; rs11105468; P = 3.4×10−11). Finally, functional relevance of TMEM16C was demonstrated with electrophysiological experiments in wild-type and knockout rats.
PMCID: PMC4244308  PMID: 25344690
18.  Problems and challenges in relation to the treatment of patients with multimorbidity: General practitioners’ views and attitudes* 
Objective. To explore views and attitudes among general practitioners (GPs) and researchers in the field of general practice towards problems and challenges related to treatment of patients with multimorbidity. Setting. A workshop entitled Patients with multimorbidity in general practice held during the Nordic Congress of General Practice in Tampere, Finland, 2013. Subjects. A total of 180 GPs and researchers. Design. Data for this summary report originate from audio-recorded, transcribed verbatim plenary discussions as well as 76 short questionnaires answered by attendees during the workshop. The data were analysed using framework analysis. Results. (i) Complex care pathways and clinical guidelines developed for single diseases were identified as very challenging when handling patients with multimorbidity; (ii) insufficient cooperation between the professionals involved in the care of multimorbid patients underlined the GPs’ impression of a fragmented health care system; (iii) GPs found it challenging to establish a good dialogue and prioritize problems with patients within the timeframe of a normal consultation; (iv) the future role of the GP was discussed in relation to diminishing health inequality, and current payment systems were criticized for not matching the treatment patterns of patients with multimorbidity. Conclusion. The participants supported the development of a future research strategy to improve the treatment of patients with multimorbidity. Four main areas were identified, which need to be investigated further to improve care for this steadily growing patient group.
PMCID: PMC4834499  PMID: 26158584
Denmark; Finland; general practice; general practitioner; Iceland; multimorbidity; Nordic countries; primary care; qualitative study; Sweden
19.  Use of primary health care prior to a postpartum psychiatric episode 
Objective. Childbirth is a strong trigger of psychiatric episodes. Nevertheless, use of primary care before these episodes is not quantified. The aim was to study the use of general practice in Denmark from two years before to one year after childbirth in women who developed postpartum psychiatric disorders. Design. A matched cohort study was conducted including women who gave birth in the period 1996–2010. Women were divided into four groups: (i) all mothers with postpartum psychiatric episodes 0–3 months after birth, n = 939; 2: All mothers with a postpartum psychiatric episode 3–12 months after birth, n = 1 436; and (iii) two comparison groups of mothers, total n = 6 630 among 320 620 eligible women. Setting. Denmark. Subjects. Women born in Denmark after 1 January 1960, restricting the cohort to women who gave birth to their first singleton child between 1 January 1996 and 20 October 2010. Main outcome measures. The main outcome measures were consultation rates, consultation rate ratios, and rate differences. Results. Women who developed a psychiatric episode after childbirth had higher GP consultation rates before, during, and after the pregnancy. Women with a psychiatric episode 0–3 months postpartum had 6.89 (95% CI 6.60; 7.18) mean number of consultations during pregnancy, corresponding to 1.52 (95% CI 1.22; 1.82) more visits than the comparison group. Conclusion. Women with a postpartum psychiatric episode had higher use of GP-based primary health care services years before the childbirth, and in this specific group of patients childbirth itself triggered a marked increase in the number of GP contacts postpartum.
PMCID: PMC4834500  PMID: 26174691
Denmark; depression; general practice; mental disorders; mental health; mothers; patient compliance; postpartum; prenatal care; primary health care
20.  Socioeconomic Position, Type 2 Diabetes and Long-Term Risk of Death 
PLoS ONE  2015;10(5):e0124829.
Both socioeconomic position (SEP) and type 2 diabetes have previously been found to be associated with mortality; however, little is known about the association between SEP, type 2 diabetes and long-term mortality when comorbidity is taken into account.
We conducted a population-based cohort study of all Danish citizens aged 40-69 years with no history of diabetes during 2001-2006 (N=2,330,206). The cohort was identified using nationwide registers, and it was followed for up to 11 years (mean follow-up was 9.5 years (SD: 2.6)). We estimated the age-standardised mortality rate (MR) and performed Poisson regression to estimate the mortality-rate-ratio (MRR) by educational level, income and cohabiting status among people with and without type 2 diabetes.
We followed 2,330,206 people for 22,971,026 person-years at risk and identified 139,681 individuals with type 2 diabetes. In total, 195,661 people died during the study period; 19,959 of these had type 2 diabetes. The age-standardised MR increased with decreasing SEP both for people with and without diabetes. Type 2 diabetes and SEP both had a strong impact on the overall mortality; the combined effect of type 2 diabetes and SEP on mortality was additive rather than multiplicative. Compared to women without diabetes and in the highest income quintile, the MRR’s were 2.8 (95%CI 2.6, 3.0) higher for women with type 2 diabetes in the lowest income quintile, while diabetes alone increased the risk of mortality 2.0 (95%CI 1.9, 2.2) times and being in the lowest income quintile without diabetes 1.8 (95%CI 1.7,1.9) times after adjusting for comorbidity. For men, the MRR’s were 2.7 (95%CI 2.5,2.9), 1.9 (95%CI 1.8,2.0) and 1.8 (95%CI 1.8,1.9), respectively.
Both Type 2 diabetes and SEP were associated with the overall mortality. The relation between type 2 diabetes, SEP, and all-cause mortality was only partly explained by comorbidity.
PMCID: PMC4420496  PMID: 25942435
21.  Adverse pregnancy outcomes after exposure to methylphenidate or atomoxetine during pregnancy 
Clinical Epidemiology  2015;7:139-147.
To determine if prenatal exposure to methylphenidate (MPH) or atomoxetine (ATX) increases the risk of adverse pregnancy outcomes in women with attention deficit/hyperactivity disorder (ADHD).
Materials and methods
This was a population-based cohort study of all pregnancies in Denmark from 1997 to 2008. Information on use of ADHD medication, ADHD diagnosis, and pregnancy outcomes was obtained from nationwide registers.
We identified 989,932 pregnancies, in which 186 (0.02%) women used MPH/ATX and 275 (0.03%) women had been diagnosed with ADHD but who did not take MPH/ATX. Our reference pregnancies had no exposure to MPH/ATX and no ADHD diagnosis. Exposure to MPH/ATX was associated with an increased risk of spontaneous abortion (SA; ie, death of an embryo or fetus in the first 22 weeks of gestation) (adjusted relative risk [aRR] 1.55, 95% confidence interval [CI] 1.03–2.36). The risk of SA was also increased in pregnancies where the mother had ADHD but did not use MPH/ATX (aRR 1.56, 95% CI 1.11–2.20). The aRR of Apgar scores <10 was increased among exposed women (aRR 2.06, 95% CI 1.11–3.82) but not among unexposed women with ADHD (aRR 0.99, 95% CI 0.48–2.05).
MPH/ATX was associated with a higher risk of SA, but our study indicated that it may at least partly be explained by confounding by indication. Treatment with MPH/ATX was however associated with low Apgar scores <10, an association not found among women with ADHD who did not use MPH/ATX.
PMCID: PMC4317061  PMID: 25657597
attention deficit/hyperactivity disorder; ADHD; methylphenidate; atomoxetine; pregnancy outcomes
22.  The 30-day prognosis of chronic-disease patients after contact with the out-of-hours service in primary healthcare 
Objective. Little is known about the prognosis of patients with chronic disease who contact the out-of-hours (OOH) service in primary care. The characteristics of contacts with the Danish out-of-hours service and daytime general practice, hospitalization, and death were studied during a 30-day follow-up period in patients with chronic heart diseases. Design. Cohort study. Setting and subjects. The study was based on data from 11 897 adults aged 18 + years from a Danish survey of OOH contacts, including information on consultation type. Reason for encounter (RFE) was categorized by OOH GPs at triage as either “exacerbation” or “new health problem”. Registry data were used to identify eligible patients, and the cohort was followed for 30 days after OOH contact through nationwide registries on healthcare use and mortality. Main outcome measures. The 30-day prognosis of chronic-disease patients after OOH contact. Results. Included patients with chronic disease had a higher risk of new OOH contact, daytime GP contact, and hospitalization than other patients during the 30-day follow-up period. OOH use was particularly high among patients with severe mental illness. A strong association was seen between chronic disease and risk of dying during follow-up. Conclusion. Patients with chronic disease used both daytime general practice and the out-of-hours service more often than others during the 30-day follow-up period; they were more often hospitalized and had higher risk of dying. The findings call for a proactive approach to future preventive day care and closer follow-up of this group, especially patients with psychiatric disease.
PMCID: PMC4278395  PMID: 25471829
Chronic disease; Denmark; general practice; OOH; out-of-hours service; primary healthcare; reasons for encounter
23.  Daytime use of general practice and use of the Out-of-Hours Primary Care Service for patients with chronic disease: a cohort study 
BMC Family Practice  2014;15:156.
The importance of proactive chronic care has become increasingly evident. Yet, it is unknown whether the use of general practice (GP) during daytime may affect the use of Out-of-Hours (OOH) Primary Care Service for people with chronic disease. We aimed to analyse the association between use of daytime general practice (GP) and use of OOH services for heart disease, lung disease, diabetes, psychiatric disease, or cancer. In particular, we intended to study the association between OOH contacts due to chronic disease exacerbation and recent use of daytime GP.
Data comprised a random sample of contacts to the OOH services (‘LV-KOS2011’). Included patients were categorised into the following chronic diseases: heart disease, lung disease, diabetes, psychiatric disease, or cancer. Information on face-to-face contacts to daytime GP was obtained from the Danish National Health Insurance Service Registry and information about exacerbation or new episodes from the LVKOS2011 survey. Associations between number of regular daytime consultations and annual follow-up consultations during one, three, six, and 12 months prior to index contacts, and outcomes of interest were estimated by using logistic regression.
In total, 11,897 patients aged ≥ 18 years were included. Of these, 2,665 patients (22.4%) were identified with one of the five selected chronic diseases; 673 patients (5.7%) had two or more. A higher odds ratio (OR) for exacerbation as reason for encounter (RFE) at the index contact was observed among patients with psychiatric disease (OR = 2.15) and cancer (OR = 2.17) than among other patients for ≥2 daytime recent contacts. When receiving an annual follow-up, exacerbation OR at index contact lowered for patients with lung disease (OR = 0.68), psychiatric disease (OR = 0.42), or ≥2 diseases (OR = 0.61).
Recent and frequent use of daytime GP for patients with the selected chronic diseases was associated with contacts to the OOH services due to exacerbation. These findings indicate that the most severely chronically ill patients tend to make more use of general practice. The provision of an annual follow-up daytime GP consultation may indicate a lower risk of contacting OOH due to exacerbation.
PMCID: PMC4262984  PMID: 25238694
24.  Use of antiepileptic drugs during pregnancy and risk of spontaneous abortion and stillbirth: population based cohort study 
The BMJ  2014;349:g5159.
Objective To determine whether use of antiepileptic drugs during pregnancy may increase the risk of spontaneous abortion or stillbirth.
Design Population based cohort study.
Setting Register based study in Denmark, 1997-2008.
Participants 983 305 pregnancies identified in the Danish medical birth register and the Danish national hospital discharge register from 1 February 1997 to 31 December 2008 were linked to the Danish Register of Medicinal Product Statistics to obtain information on use of antiepileptic drugs.
Main outcome measures Risk ratio of spontaneous abortion and stillbirth after use of antiepileptic drugs during pregnancy, estimated by using binomial regression adjusting for potential confounders of maternal age, cohabitation, income, education, history of severe mental disorder, and history of drug misuse.
Results Antiepileptic drugs were used in a total of 4700 (0.5%) pregnancies. 16 out of 100 pregnant women using antiepileptics and 13 out of 100 pregnant women not using antiepileptics experienced a spontaneous abortion. After adjusting for potential confounders pregnant women using antiepileptics had a 13% higher risk of spontaneous abortions than pregnant women not using antiepileptics (adjusted risk ratio 1.13, 95% confidence interval 1.04 to 1.24). However, the risk of spontaneous abortion was not increased in women with an epilepsy diagnosis (0.98, 0.87 to 1.09), only in women without a diagnosis of epilepsy (1.30, 1.14 to 1.49). In an analysis including women with at least two pregnancies with discordant antiepileptic drug use (for example, use in the first pregnancy but not in the second), the adjusted hazard ratio for spontaneous abortion was 0.83 (0.69 to 1.00) for exposed pregnancies compared with unexposed pregnancies. Stillbirth was identified in 18 women who used antiepileptic drugs (unadjusted risk ratio 1.29, 0.80 to 2.10).
Conclusion Among women with epilepsy and when analysing the risk in antiepileptic drug discordant pregnancies in the same woman, we found no overall association between the use of antiepileptic drugs during pregnancy and spontaneous abortions. Therefore unmeasured confounding may explain the slight increased risk for spontaneous abortion with any antiepileptic drug use (among women both with and without epilepsy). We found no association between antiepileptic drug use during pregnancy and stillbirth, but the statistical precision was low.
PMCID: PMC4141333  PMID: 25150301
25.  Mortality after Parental Death in Childhood: A Nationwide Cohort Study from Three Nordic Countries 
PLoS Medicine  2014;11(7):e1001679.
Jiong Li and colleagues examine mortality rates in children who lost a parent before 18 years old compared with those who did not using population-based data from Denmark, Sweden, and Finland.
Please see later in the article for the Editors' Summary
Bereavement by spousal death and child death in adulthood has been shown to lead to an increased risk of mortality. Maternal death in infancy or parental death in early childhood may have an impact on mortality but evidence has been limited to short-term or selected causes of death. Little is known about long-term or cause-specific mortality after parental death in childhood.
Methods and Findings
This cohort study included all persons born in Denmark from 1968 to 2008 (n = 2,789,807) and in Sweden from 1973 to 2006 (n = 3,380,301), and a random sample of 89.3% of all born in Finland from 1987 to 2007 (n = 1,131,905). A total of 189,094 persons were included in the exposed cohort when they lost a parent before 18 years old. Log-linear Poisson regression was used to estimate mortality rate ratio (MRR). Parental death was associated with a 50% increased all-cause mortality (MRR = 1.50, 95% CI 1.43–1.58). The risks were increased for most specific cause groups and the highest MRRs were observed when the cause of child death and the cause of parental death were in the same category. Parental unnatural death was associated with a higher mortality risk (MRR = 1.84, 95% CI 1.71–2.00) than parental natural death (MRR = 1.33, 95% CI 1.24–1.41). The magnitude of the associations varied according to type of death and age at bereavement over different follow-up periods. The main limitation of the study is the lack of data on post-bereavement information on the quality of the parent-child relationship, lifestyles, and common physical environment.
Parental death in childhood or adolescence is associated with increased all-cause mortality into early adulthood. Since an increased mortality reflects both genetic susceptibility and long-term impacts of parental death on health and social well-being, our findings have implications in clinical responses and public health strategies.
Please see later in the article for the Editors' Summary
Editors' Summary
When someone close dies, it is normal to grieve, to mourn the loss of that individual. Initially, people who have lost a loved one often feel numb and disorientated and find it hard to grasp what has happened. Later, people may feel angry or guilty, and may be overwhelmed by feelings of sadness and despair. They may become depressed or anxious and may even feel suicidal. People who are grieving can also have physical reactions to their loss such as sleep problems, changes in appetite, and illness. How long bereavement—the period of grief and mourning after a death—lasts and how badly it affects an individual depends on the relationship between the individual and the deceased person, on whether the death was expected, and on how much support the mourner receives from relatives, friends, and professionals.
Why Was This Study Done?
The loss of a life-partner or of a child is associated with an increased risk of death (mortality), and there is also some evidence that the death of a parent during childhood leads to an increased mortality risk in the short term. However, little is known about the long-term impact on mortality of early parental loss or whether the impact varies with the type of death—a natural death from illness or an unnatural death from external causes such as an accident—or with the specific cause of death. A better understanding of the impact of early bereavement on mortality is needed to ensure that bereaved children receive appropriate health and social support after a parent's death. Here, the researchers undertake a nationwide cohort study in three Nordic countries to investigate long-term and cause-specific mortality after parental death in childhood. A cohort study compares the occurrence of an event (here, death) in a group of individuals who have been exposed to a particular variable (here, early parental loss) with the occurrence of the same event in an unexposed cohort.
What Did the Researchers Do and Find?
The researchers obtained data on everyone born in Denmark from 1968 to 2008 and in Sweden from 1973 to 2006, and on most people born in Finland from 1987 to 2007 (more than 7 million individuals in total) from national registries. They identified 189,094 individuals who had lost a parent between the age of 6 months and 18 years. They then estimated the mortality rate ratio (MRR) associated with parental death during childhood or adolescence by comparing the number of deaths in this exposed cohort (after excluding children who died on the same day as a parent or shortly after from the same cause) and in the unexposed cohort. Compared with the unexposed cohort, the exposed cohort had 50% higher all-cause mortality (MRR = 1.50). The risk of mortality in the exposed cohort was increased for most major categories of cause of death but the highest MRRs were seen when the cause of death in children, adolescents, and young adults during follow-up and the cause of parental death were in the same category. Notably, parental unnatural death was associated with a higher mortality risk (MRR = 1.84) than parental natural death (MRR = 1.33). Finally, the exposed cohort had increased all-cause MRRs well into early adulthood irrespective of child age at parental death, and the magnitude of MRRs differed by child age at parental death and by type of death.
What Do These Findings Mean?
These findings show that in three high-income Nordic countries parental death during childhood and adolescence is associated with an increased risk of all-cause mortality into early adulthood, irrespective of sex and age at bereavement and after accounting for baseline characteristics such as socioeconomic status. Part of this association may be due to “confounding” factors—the people who lost a parent during childhood may have shared other unknown characteristics that increased their risk of death. Because the study was undertaken in high-income countries, these findings are unlikely to be the result of a lack of material or health care needs. Rather, the increased mortality among the exposed group reflects both genetic susceptibility and the long-term impacts of parental death on health and social well-being. Given that increased mortality probably only represents the tip of the iceberg of the adverse effects of early bereavement, these findings highlight the need to provide long-term health and social support to bereaved children.
Additional Information
Please access these websites via the online version of this summary at
The UK National Health Service Choices website provides information about bereavement, including personal stories; it also provides information about children and bereavement and about young people and bereavement, including links to not-for-profit organizations that support children through bereavement
The US National Cancer Institute has detailed information about dealing with bereavement for the public and for health professionals that includes a section on children and grief (in English and Spanish)
The US National Alliance for Grieving Children promotes awareness of the needs of children and teens grieving a death and provides education and resources for anyone who wants to support them
MedlinePlus provides links to other resources about bereavement (in English and Spanish)
PMCID: PMC4106717  PMID: 25051501

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