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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  Chronic-disease patients and their use of out-of-hours primary health care: a cross-sectional study 
BMC Family Practice  2014;15:114.
The general practitioner (GP) plays an important role for chronic disease care. Continuous and close contact with daytime general practice is intended to prevent medical problems arising outside office hours due to already diagnosed chronic disease. However, previous studies indicate that patients with chronic diseases are frequent users of out-of-hours primary care services (OOH), but knowledge is limited on reasons for encounter (RFE), severity of symptoms, and OOH patient handling. We aimed to describe contacts to the OOH services from patients with chronic heart disease, lung disease, severe psychiatric disorders, diabetes, and cancer in terms of RFE, OOH GP diagnosis, assessed severity of symptoms, and actions taken by the GP.
Eligible patients (aged 18 years and older) were randomly sampled from a one-year cross-sectional study comprising 15,229 contacts to the OOH services in the Central Denmark Region. A cohort of patients with one or more of the five selected chronic diseases were identified by linking data on the Danish civil registration number (CPR) through specific nationwide Danish health registers.
Out of 13,930 identified unique patients, 4,912 had at least one of the five chronic diseases. In total, 25.9% of all calls to the OOH services came from this chronic disease patient group due to an acute exacerbation; 32.6% of these calls came from patients with psychiatric diagnoses. Patients with chronic disease were more likely to receive a face-to-face contact than the remaining group of patients, except for calls from patients with a psychiatric disorder who were more often completed through a telephone consultation. Patients with heart disease calling due to a new health problem formed the largest proportion of all OOH referrals to hospital (13.3%) compared to calls from the other groups with chronic disease (3.4-6.7%).
A third of the patients randomly sampled by their OOH call had one or more of the five selected chronic diseases (i.e. chronic lung disease, heart disease, diabetes, psychiatric disease, or cancer). Patients with chronic disease were more often managed by OOH GPs than other patients.
PMCID: PMC4064509  PMID: 24912378
Out-of-hours services; OOH; Chronic disease; General practice; Primary health care; Reasons for encounter
10.  Psychiatric disorders following fetal death: a population-based cohort study 
BMJ Open  2014;4(6):e005187.
Women have increased risks of severe mental disorders after childbirth and death of a child, but it remains unclear whether this association also applies to fetal loss and, if so, to which extent. We studied the risk of any inpatient or outpatient psychiatric treatment during the time period from 12 months before to 12 months after fetal death.
Cohort study using Danish population-based registers.
A total of 1 112 831 women born in Denmark from 1960 to 1995 were included. In total, 87 687cases of fetal death (International Classification of Disease-10 codes for spontaneous abortion or stillbirth) were recorded between 1996 and 2010.
Primary and secondary outcome measures
The main outcome measures were incidence rate ratios (risk of first psychiatric inpatient or outpatient treatment).
A total of 1379 women had at least one psychiatric episode during follow-up from the year before fetal death to the year after. Within the first few months after the loss, women had an increased risk of psychiatric contact, IRR: 1.51 (95% CI 1.15 to 1.99). In comparison, no increased risk of psychiatric contact was found for the period before fetal death. The risk of experiencing a psychiatric episode was highest for women with a loss occurring after 20 weeks of gestation (12 month probability: 1.95%, 95% CI 1.50 to 2.39).
Fetal death was associated with a transient increased risk of experiencing a first-time episode of a psychiatric disorder, primarily adjustment disorders. The risk of psychiatric episodes tended to increase with increasing gestational age at the time of the loss.
PMCID: PMC4054628  PMID: 24907247
Epidemiology; Obstetrics; Psychiatry
11.  Post-Stroke Mortality, Stroke Severity, and Preadmission Antipsychotic Medicine Use – A Population-Based Cohort Study 
PLoS ONE  2014;9(1):e84103.
Background and Purpose
It has been suggested that antipsychotic medication may be neuroprotective and may reduce post-stroke mortality, but studies are few and ambiguous. We aimed to investigate the post-stroke effects of preadmission antipsychotic use.
We conducted a nationwide, population-based cohort study of 81,143 persons admitted with stroke in Denmark from 2003–2010. Using Danish health care databases, we extracted data on preadmission use of antipsychotics and confounding factors. We examined the association between current, former, and never use of antipsychotics and stroke severity, length of hospital stay, and 30-day post-stroke mortality using logistic regression analysis, survival analysis, and propensity score matching.
Current users of antipsychotics had a higher risk of severe or very severe stroke on The Scandinavian Stroke Scale than never users of antipsychotics (adjusted odds ratios, 1.43; 95% CI, 1.29–1.58). Current users were less likely to be discharged from hospital within 30 days of admission than never users (probability of non-discharge, 27.0% vs. 21.9%). Antipsychotics was associated with an increased 30-day post-stroke mortality among current users (adjusted mortality rate ratios, 1.42; 95% CI, 1.29–1.55), but not among former users (adjusted mortality rate ratios, 1.05; 95% CI, 0.98–1.14).
Preadmission use of antipsychotics was associated with a higher risk of severe stroke, a longer duration of hospital stay, and a higher post-stroke mortality, even after adjustment for known confounders. Antipsychotics play an important role in the treatment of many psychiatric conditions, but our findings do not support the hypothesis that they reduce stroke severity or post-stroke mortality.
PMCID: PMC3885530  PMID: 24416196
12.  Antidepressant exposure in pregnancy and risk of autism spectrum disorders 
Clinical Epidemiology  2013;5:449-459.
Both the use of antidepressant medication during pregnancy and the prevalence of autism spectrum disorder have increased during recent years. A causal link has recently been suggested, but the association may be confounded by the underlying indication for antidepressant use. We investigated the association between maternal use of antidepressant medication in pregnancy and autism, controlling for potential confounding factors.
We identified all children born alive in Denmark 1996–2006 (n=668,468) and their parents in the Danish Civil Registration System. We obtained information on the mother’s prescriptions filled during pregnancy from the Danish National Prescription Registry, and on diagnoses of autism spectrum disorders in the children and diagnoses of psychiatric disorders in the parents from the Danish Psychiatric Central Register. In a cohort analysis, we estimated hazard ratios of autism spectrum disorders in children exposed to antidepressant medication during pregnancy compared with children who were not exposed, using Cox proportional hazards regression analysis. Furthermore, we estimated the risk for autism spectrum disorder in a sibling design.
Children exposed prenatally to antidepressants had an adjusted hazard ratio of 1.5 (95% confidence interval [CI] 1.2–1.9) for autism spectrum disorder compared with unexposed children. Restricting the analysis to children of women with a diagnosis of affective disorder, the adjusted hazard ratio was 1.2 (95% CI 0.7–2.1), and the risk was further reduced when exposed children were compared with their unexposed siblings (adjusted hazard ratio 1.1; 95% CI 0.5–2.3).
After controlling for important confounding factors, there was no significant association between prenatal exposure to antidepressant medication and autism spectrum disorders in the offspring.
PMCID: PMC3832387  PMID: 24255601
antidepressants; depression; autism; autism spectrum disorder; childhood autism; pregnancy
13.  Depressive Symptoms and Risk of New Cardiovascular Events or Death in Patients with Myocardial Infarction: A Population-Based Longitudinal Study Examining Health Behaviors and Health Care Interventions 
PLoS ONE  2013;8(9):e74393.
Depressive symptoms is associated with adverse cardiovascular outcomes in patients with myocardial infarction (MI), but the underlying mechanisms are unclear and it remains unknown whether subgroups of patients are at a particularly high relative risk of adverse outcomes. We examined the risk of new cardiovascular events and/or death in patients with depressive symptoms following first-time MI taking into account other secondary preventive factors. We further explored whether we could identify subgroups of patients with a particularly high relative risk of adverse outcomes.
Methods and Results
We conducted a prospective population-based cohort study of 897 patients discharged with first-time MI between 1 January 2009 and 31 December 2009, and followed up until 31 July 2012. Depressive symptoms were found in 18.6% using the Hospital Anxiety and Depression Scale (HADS-D≥8). A total of 239 new cardiovascular events, 95 deaths, and 288 composite events (239 new cardiovascular events and 49 deaths) occurred during 1,975 person-years of follow-up. Event-free survival was evaluated using Cox regression analysis. Compared to the 730 patients without depressive symptoms (HADS-D<8), the 167 patients with depressive symptoms (HADS-D≥8) had age- and sex-adjusted hazard ratios [HR] (95% confidence interval [CI]) of 1.53 (95% CI, 1.14–2.05) for a new cardiovascular event, 3.10 (95% CI, 2.04–4.71) for death and 1.77 (95% CI, 1.36–2.31) for a composite event. The associations were attenuated when adjusted for disease severity, comorbid conditions and physical inactivity; HR = 1.17 (95% CI, 0.85–1.61) for a new cardiovascular event, HR = 2.01 (95% CI, 1.28–3.16) for death, and HR = 1.33 (95% CI, 1.00–1.76) for a composite event. No subgroups of patients had a particularly high risk of adverse outcomes.
Depressive symptoms following first-time MI was an independent prognostic risk factor for death, but not for new cardiovascular events. We found no subgroups of patients with a particularly high relative risk of adverse outcomes.
PMCID: PMC3783427  PMID: 24086339
14.  Prenatal Antidepressant Exposure and Risk of Spontaneous Abortion – A Population-Based Study 
PLoS ONE  2013;8(8):e72095.
To estimate the risk of spontaneous abortion after use of antidepressant medication during pregnancy.
From the Danish Medical Birth Registry and the Danish National Hospital Registry, we identified all pregnancies leading to in- or outpatient contacts in Denmark from February 1997 to December 2008. The Danish Registry of Medicinal Product Statistics provided information on the women's prescriptions for antidepressants during pregnancy. We obtained information on women who were diagnosed with depression from the Danish Psychiatric Central Registry. Adjusted relative risks (aRR) of spontaneous abortion were estimated according to exposure to antidepressants or maternal depression using binomial regression.
Of the 1,005,319 pregnancies (547,300 women) identified, 114,721 (11.4%) ended in a spontaneous abortion. We identified 22,061 pregnancies exposed to antidepressants and 1,843 with a diagnosis of depression with no antidepressant use, of which 2,637 (12.0%) and 205 (11.1%) ended in a spontaneous abortion, respectively. Antidepressant exposure was associated with an aRR of 1.14 (95% confidence interval (CI) 1.10–1.18) for spontaneous abortion compared with no exposure to antidepressants. Among women with a diagnosis of depression, the aRR for spontaneous abortion after any antidepressant exposure was 1.00 (95% CI 0.80–1.24). No individual selective serotonin reuptake inhibitor (SSRI) was associated with spontaneous abortions. In unadjusted analyses, we found that mirtazapine, venlafaxine, and duloxetine were associated with spontaneous abortions among women with depression but we had no information on potential differences in disease severity and only few pregnancies were exposed in the population.
We identified a slightly increased risk of spontaneous abortion associated with the use of antidepressants during pregnancy. However, among women with a diagnosis of depression, antidepressants in general or individual SSRI in particular were not associated with spontaneous abortions. Further studies are warranted on the newer non-SSRI antidepressants, as we had insufficient data to adjust for important confounding factors.
PMCID: PMC3756033  PMID: 24015208
15.  Correction: Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2013;8(8):10.1371/annotation/dbd21894-4722-499c-afaf-b03015fae7d8.
PMCID: PMC3744642
16.  Mental health status and risk of new cardiovascular events or death in patients with myocardial infarction: a population-based cohort study 
BMJ Open  2013;3(8):e003045.
To examine the association between mental health status after first-time myocardial infarction (MI) and new cardiovascular events or death, taking into account depression and anxiety as well as clinical, sociodemographic and behavioural risk factors.
Population-based cohort study based on questionnaires and nationwide registries. Mental health status was assessed 3 months after MI using the Mental Component Summary score from the Short-Form 12 V.2.
Central Denmark Region.
All patients hospitalised with first-time MI from 1 January 2009 through 31 December 2009 (n=880). The participants were categorised in quartiles according to the level of mental health status (first quartile=lowest mental health status).
Main outcome measures
Composite endpoint of new cardiovascular events (MI, heart failure, stroke/transient ischaemic attack) and all-cause mortality.
During 1940 person-years of follow-up, 277 persons experienced a new cardiovascular event or died. The cumulative incidence following 3 years after MI increased consistently with decreasing mental health status and was 15% (95% CI 10.8% to 20.5%) for persons in the fourth quartile, 29.1% (23.5% to 35.6%) in the third quartile, 37.0% (30.9% to 43.9%) in the second quartile, and 47.5% (40.9% to 54.5%) in the first quartile. The HRs were high, even after adjustments for age, sociodemographic characteristics, cardiac disease severity, comorbidity, secondary prophylactic medication, smoking status, physical activity, depression and anxiety (HR3rd quartile 1.90 (95% CI 1.23 to 2.93), HR2nd quartile 2.14 (1.37 to 3.33), HR1st quartile 2.23 (1.35 to 3.68) when using the fourth quartile as reference).
Low mental health status following first-time MI was independently associated with an increased risk of new cardiovascular events or death. Further research is needed to disentangle the pathways that link mental health status following MI to prognosis and to identify interventions that can improve mental health status and prognosis.
PMCID: PMC3733312  PMID: 23913773
Cardiology; Myocardial Infarction < Cardiology; Mental Health; Epidemiology
17.  Maternal Use of Antibiotics and the Risk of Childhood Febrile Seizures: A Danish Population-Based Cohort 
PLoS ONE  2013;8(4):e61148.
In a large population-based cohort in Denmark to examine if maternal use of antibiotics during pregnancy, as a marker of infection, increases the risk of febrile seizures in childhood in a large population-based cohort in Denmark.
All live-born singletons born in Denmark between January 1, 1996 and September 25, 2004 and who were alive on the 90th day of life were identified from the Danish National Birth Registry. Diagnoses of febrile seizures were obtained from the Danish National Hospital Register and maternal use of antibiotics was obtained from the National Register of Medicinal Product Statistics. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated by Cox proportional hazard regression models.
We followed 551,518 singletons for up to 5 years and identified a total of 21,779 children with a diagnosis of febrile seizures. Slightly increased hazard ratios were observed among most exposure groups when compared to the unexposed group, ex. HR 1.08 95% CI: 1.05–1.11 for use of any systemic antibiotic during pregnancy.
We found weak associations between the use of pharmacologically different antibiotics during pregnancy and febrile seizures in early childhood which may indicate that some infections, or causes or effects of infections, during pregnancy could affect the fetal brain and induce susceptibility to febrile seizures.
PMCID: PMC3627381  PMID: 23613800
18.  Prenatal Exposure to Bereavement and Type-2 Diabetes: A Danish Longitudinal Population Based Study 
PLoS ONE  2012;7(8):e43508.
The etiology of type-2 diabetes is only partly known, and a possible role of prenatal stress in programming offspring for insulin resistance has been suggested by animal models. Previously, we found an association between prenatal stress and type-1 diabetes. Here we examine the association between prenatal exposure to maternal bereavement during preconception and pregnancy and development of type-2 diabetes in the off-spring.
We utilized data from the Danish Civil Registration System to identify singleton births in Denmark born January 1st 1979 through December 31st 2008 (N = 1,878,246), and linked them to their parents, grandparents, and siblings. We categorized children as exposed to bereavement during prenatal life if their mothers lost an elder child, husband or parent during the period from one year before conception to the child’s birth. We identified 45,302 children exposed to maternal bereavement; the remaining children were included in the unexposed cohort. The outcome of interest was diagnosis of type-2 diabetes. We estimated incidence rate ratios (IRRs) from birth using log-linear poisson regression models and used person-years as the offset variable. All models were adjusted for maternal residence, income, education, marital status, sibling order, calendar year, sex, and parents’ history of diabetes at the time of pregnancy.
We found children exposed to bereavement during their prenatal life were more likely to have a type-2 diabetes diagnosis later in life (aIRR: 1.31, 1.01–1.69). These findings were most pronounced when bereavement was caused by death of an elder child (aIRR: 1.51, 0.94–2.44). Results also indicated the second trimester of pregnancy to be the most sensitive period of bereavement exposure (aIRR:2.08, 1.15–3.76).
Our data suggests that fetal exposure to maternal bereavement during preconception and the prenatal period may increase the risk for developing type-2 diabetes in childhood and young adulthood.
PMCID: PMC3429491  PMID: 22952698
19.  The 5-minute Apgar score as a predictor of childhood cancer: a population-based cohort study in five million children 
BMJ Open  2012;2(4):e001095.
The aetiology of childhood cancer remains largely unknown but recent research indicates that uterine environment plays an important role. We aimed to examine the association between the Apgar score at 5 min after birth and the risk of childhood cancer.
Nationwide population-based cohort study.
Nationwide register data in Denmark and Sweden.
Study population
All live-born singletons born in Denmark from 1978 to 2006 (N=1 771 615) and in Sweden from 1973 to 2006 (N=3 319 573). Children were followed up from birth to 14 years of age.
Main outcome measures
Rates and HRs for all childhood cancers and for specific childhood cancers.
A total of 8087 children received a cancer diagnosis (1.6 per 1000). Compared to children with a 5-min Apgar score of 9–10, children with a score of 0–5 had a 46% higher risk of cancer (adjusted HR 1.46, 95% CI 1.15 to 1.89). The potential effect of low Apgar score on overall cancer risk was mostly confined to children diagnosed before 6 months of age. Children with an Apgar score of 0–5 had higher risks for several specific childhood cancers including Wilms’ tumour (HR 4.33, 95% CI 2.42 to 7.73).
A low 5 min Apgar score was associated with a higher risk of childhood cancers diagnosed shortly after birth. Our data suggest that environmental factors operating before or during delivery may play a role on the development of several specific childhood cancers.
PMCID: PMC3425910  PMID: 22874628
Oncology; Epidemiology; Paediatric oncology; Preventive Medicine
20.  Chronic care management in Danish general practice - a cross‒sectional study of workload and multimorbidity 
BMC Family Practice  2012;13:52.
About 30% of the Danish population has one or more chronic conditions, and general practitioners (GPs) play a key role in effective chronic care management. However, little is known about these encounters in general practice. The aim was to describe the frequency of patients with one or more chronic conditions in general practice and how these consultations were experienced by the GPs.
All GPs in the Central Denmark Region were invited to register all contacts during one day in the 12‒month study period from December; 404 (46%) accepted. For each patient contact, the GPs were asked to fill in a one‒page registration form covering information on chronic disease, reason for encounter, diagnosis, number of additional psychosocial problems raised by the patient during the consultation, time consumption, experienced burden of the consultation, referral to specialized care, and whether a nurse could have substituted the GP. Patients were categorized according to the number of chronic conditions (none, one, two, three or more) and the categories compared with regard to the GP‒experienced burden of the contacts. Moreover, we examined which chronic conditions posed the the greatest challenge to the GPs.
Patients aged 40 years or more had a total of 8,236 contacts. Among these patients 2,849 (34.6%; 95% CI 33.6‒35.6) had one and 2,596 (31.5%; CI 30.5‒32.5) had more than one chronic disease. The time consumption and the burden of their contacts tended to rise with the number of chronic conditions. Being present in 22.9% (CI 21.6‒24.3) of all face‒to‒face contacts, hypertension was the most common chronic condition. The burden of the contacts was experienced as particularly heavy for patients with depression and dementia due to more additional psychosocial problems and the time consumption.
General practitioners considered consultations with multimorbid patients demanding and not easily delegated to nurses. As the number of patients with chronic conditions and multimorbidity is increasing, GPs can be expected to face a heavier workload in the future.
PMCID: PMC3436724  PMID: 22676446
Primary care; Chronic disease; Multimorbidity; Workload
21.  Long-Term Health Outcomes in Children Born to Mothers with Diabetes: A Population-Based Cohort Study 
PLoS ONE  2012;7(5):e36727.
To examine whether prenatal exposure to parental type 1 diabetes, type 2 diabetes, or gestational diabetes is associated with an increased risk of malignant neoplasm or diseases of the circulatory system in the offspring.
Methods/Principal Findings
We conducted a population-based cohort study of 1,781,576 singletons born in Denmark from 1977 to 2008. Children were followed for up to 30 years from the day of birth until the onset of the outcomes under study, death, emigration, or December 31, 2009, whichever came first. We used Cox proportional hazards model to estimate hazard ratios (HR) with 95% confidence intervals (95% CI) for the outcomes under study while adjusting for potential confounders. An increased risk of malignant neoplasm was found in children prenatally exposed to maternal type 2 diabetes (HR = 2.2, 95%CI: 1.5–3.2). An increased risk of diseases of the circulatory system was found in children exposed to maternal type 1 diabetes (HR = 2.2, 95%CI: 1.6–3.0), type 2 diabetes (HR = 1.4, 95%CI: 1.1–1.7), and gestational diabetes (HR = 1.3, 95%CI: 1.1–1.6), but results were attenuated after excluding children with congenital malformations. An increased risk of diseases of the circulatory system was also found in children exposed to paternal type 2 diabetes (HR = 1.5, 95%CI: 1.1–2.2) and the elevated risk remained after excluding children with congenital malformations.
This study suggests that susceptibility to malignant neoplasm is modified partly by fetal programming. Diseases of the circulatory system may be modified by genetic factors, other time-stable family factors, or fetal programming.
PMCID: PMC3359312  PMID: 22649497
22.  Rehabilitation status three months after first-time myocardial infarction 
To describe the rehabilitation status three months after first-time myocardial infarction (MI) to identify focus areas for long-term cardiac rehabilitation (CR) in general practice.
Population-based cross-sectional study.
Setting and subjects
Patients with first-time MI in 2009 from the Central Denmark Region. Data were obtained from patient questionnaires and from registers.
Of the 1288 eligible patients, 908 (70.5%) responded. The mean (SD) age was 67.1 (11.7) years and 626 (68.9%) were men. Overall, 287 (31.6%) of the patients lived alone and 398 (45.4%) had less than 10 years of education. Upwards of half (58.5%) of the patients stated that they had participated in hospital-based rehabilitation shortly after admission. A total of 262 (29.2%) were identified with anxiety or depressive disorder or both, according to the Hospital Anxiety and Depression Scale. Of these, 78 (29.8%) reported that they had participated in psychosocial support, and 55 (21.0%) used antidepressants. One in five patients smoked three months after MI although nearly half of the smokers had stopped after the MI. Regarding cardioprotective drugs, 714 (78.6%) used aspirin, 694 (76.4%) clopidogrel, 756 (83.3%) statins, and 735 (81.0%) beta-blockers.
After three months, there is a considerable potential for further rehabilitation of MI patients. In particular, the long-term CR should focus on mental health, smoking cessation, and cardioprotective drugs.
PMCID: PMC3308468  PMID: 22126219
Depression; drug therapy; family practice; myocardial infarction; rehabilitation; smoking
23.  Drug-induced mild therapeutic hypothermia obtained by administration of a transient receptor potential vanilloid type 1 agonist 
The use of mechanical/physical devices for applying mild therapeutic hypothermia is the only proven neuroprotective treatment for survivors of out of hospital cardiac arrest. However, this type of therapy is cumbersome and associated with several side-effects. We investigated the feasibility of using a transient receptor potential vanilloid type 1 (TRPV1) agonist for obtaining drug-induced sustainable mild hypothermia.
First, we screened a heterogeneous group of TRPV1 agonists and secondly we tested the hypothermic properties of a selected candidate by dose-response studies. Finally we tested the hypothermic properties in a large animal. The screening was in conscious rats, the dose-response experiments in conscious rats and in cynomologus monkeys, and the finally we tested the hypothermic properties in conscious young cattle (calves with a body weight as an adult human). The investigated TRPV1 agonists were administered by continuous intravenous infusion.
Screening: Dihydrocapsaicin (DHC), a component of chili pepper, displayed a desirable hypothermic profile with regards to the duration, depth and control in conscious rats. Dose-response experiments: In both rats and cynomologus monkeys DHC caused a dose-dependent and immediate decrease in body temperature. Thus in rats, infusion of DHC at doses of 0.125, 0.25, 0.50, and 0.75 mg/kg/h caused a maximal ΔT (°C) as compared to vehicle control of -0.9, -1.5, -2.0, and -4.2 within approximately 1 hour until the 6 hour infusion was stopped. Finally, in calves the intravenous infusion of DHC was able to maintain mild hypothermia with ΔT > -3°C for more than 12 hours.
Our data support the hypothesis that infusion of dihydrocapsaicin is a candidate for testing as a primary or adjunct method of inducing and maintaining therapeutic hypothermia.
PMCID: PMC2966451  PMID: 20932337
24.  Prenatal Stress Exposure Related to Maternal Bereavement and Risk of Childhood Overweight 
PLoS ONE  2010;5(7):e11896.
It has been suggested that prenatal stress contributes to the risk of obesity later in life. In a population–based cohort study, we examined whether prenatal stress related to maternal bereavement during pregnancy was associated with the risk of overweight in offspring during school age.
Methodology/Principal Findings
We followed 65,212 children born in Denmark from 1970–1989 who underwent health examinations from 7 to 13 years of age in public or private schools in Copenhagen. We identified 459 children as exposed to prenatal stress, defined by being born to mothers who were bereaved by death of a close family member from one year before pregnancy until birth of the child. We compared the prevalence of overweight between the exposed and the unexposed. Body mass index (BMI) values and prevalence of overweight were higher in the exposed children, but not significantly so until from 10 years of age and onwards, as compared with the unexposed children. For example, the adjusted odds ratio (OR) for overweight was 1.68 (95% confidence interval [CI] 1.08–2.61) at 12 years of age and 1.63 (95% CI 1.00–2.61) at 13 years of age. The highest ORs were observed when the death occurred in the period from 6 to 0 month before pregnancy (OR 3.31, 95% CI 1.71–6.42 at age 12, and OR 2.31, 95% CI 1.08–4.97 at age 13).
Our results suggest that severe pre-pregnancy stress is associated with an increased risk of overweight in the offspring in later childhood.
PMCID: PMC2912844  PMID: 20689593
25.  Early Life Disease Programming during the Preconception and Prenatal Period: Making the Link between Stressful Life Events and Type-1 Diabetes 
PLoS ONE  2010;5(7):e11523.
To assess the risk of developing Type-1 diabetes among children who were exposed to maternal bereavement during the prenatal or 1-year preconception period.
We identified N = 1,548,746 singleton births born in Denmark between January 1st 1979 through December 31st 2004, and their next of kin. Altogether, 39,857 children were exposed to bereavement during their prenatal life. The main outcome of interest was hospitalization for type-1 diabetes (ICD 8: 249; ICD 10: E10).
We found the strongest association for type-1 diabetes among children exposed to traumatic father or sibling deaths (aIRR: 2.03, 1.22–3.38); the association was mainly seen for girls (aIRR: 2.91, 1.61–5.26).
We found evidence to suggest that female fetuses exposed to severe prenatal stress are at increased risk for developing type-1 diabetes.
PMCID: PMC2901388  PMID: 20634978

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