Exposure to risperidone versus other antipsychotics and risk of osteoporosis-related fractures: a population-based study.

OBJECTIVE: Antipsychotics may increase serum prolactin, which has particularly been observed with risperidone. Further, hyperprolactinemia has been linked to osteoporosis-related fractures. Therefore, we investigated fracture risk in a nationwide cohort exposed to antipsychotics. METHODS: Swedish registers were used to identify adults with two consecutive dispensations of risperidone (n = 38 211), other atypical antipsychotics not including paliperidone (n = 60 691), or typical antipsychotics (n = 17 445) within three months between 2006 and 2013. An osteoporosis-related fracture was defined as a non-open hip/femur fracture in primary analyses. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Risperidone users were on average older (mean age of 68, 44, and 63 years for risperidone, other atypical antipsychotics, and typical antipsychotics respectively). Compared with other atypical antipsychotics, there was no association between risperidone and osteoporosis-related fractures in the overall (HR = 1.04, CI: 0.91-1.19) or age-stratified analyses. A significantly increased risk of typical antipsychotics (HR = 1.24, CI: 1.07-1.45) compared with other atypical antipsychotics remained for ages >45 years. CONCLUSION: Risperidone does not appear to be associated with an increased risk of osteoporosis-related fracture compared with other atypical antipsychotic agents as a group. For typical antipsychotics, a moderately elevated risk of hip fractures was noted compared with other atypical antipsychotics, possibly because of residual confounding.

International trends in clozapine use: a study in 17 countries.

OBJECTIVE: There is some evidence that clozapine is significantly underutilised. Also, clozapine use is thought to vary by country, but so far no international study has assessed trends in clozapine prescribing. Therefore, this study aimed to assess clozapine use trends on an international scale, using standardised criteria for data analysis. METHOD: A repeated cross-sectional design was applied to data extracts (2005-2014) from 17 countries worldwide. RESULTS: In 2014, overall clozapine use prevalence was greatest in Finland (189.2/100 000 persons) and in New Zealand (116.3/100 000), and lowest in the Japanese cohort (0.6/100 000), and in the privately insured US cohort (14.0/100 000). From 2005 to 2014, clozapine use increased in almost all studied countries (relative increase: 7.8-197.2%). In most countries, clozapine use was highest in 40-59-year-olds (range: 0.6/100 000 (Japan) to 344.8/100 000 (Finland)). In youths (10-19 years), clozapine use was highest in Finland (24.7/100 000) and in the publicly insured US cohort (15.5/100 000). CONCLUSION: While clozapine use has increased in most studied countries over recent years, clozapine is still underutilised in many countries, with clozapine utilisation patterns differing significantly between countries. Future research should address the implementation of interventions designed to facilitate increased clozapine utilisation.

Increased susceptibility to infections before the diagnosis of immune thrombocytopenia.

BACKGROUND: Infections after diagnosis of primary chronic immune thrombocytopenia (cITP) have mostly been connected to the immunomodulation treatment. Infections may trigger autoimmune diseases and may be a complication of an already impaired immune system. OBJECTIVES: To investigate the association of cITP with infection before diagnosis. We also estimated the incidence of cITP based on the new definition by the International ITP Working Group. METHODS: We identified 1087 adults with primary cITP between 2006 and 2012 using the Swedish Patient Register. Data on infections not already associated with secondary ITP were also retrieved from the register. The standardized incidence ratios (SIRs), using the rates from the general population, and 95% confidence intervals (CIs) were estimated as a measure of relative risk. We used data from the Prescribed Drug Register to estimate SIR for anti-infective treatment. RESULTS: The incidence of cITP was 2.30 per 100 000 person-years (95% CI, 2.15-2.45). cITP was associated with an increased risk of serious infections requiring inpatient or outpatient care within 5 years before cITP diagnosis (SIR = 8.74; 95% CI, 7.47-10.18). Higher magnitude SIRs were observed for candidiasis, viral infection at an unspecified site and acute upper respiratory infections. For anti-infective drugs the SIR was 1.37 (1.25-1.50) and the highest SIRs were observed for amoxicillin, macrolides, nitrofurantoin and antivirals. CONCLUSION: Patients with cITP have increased risks of infection and anti-infective treatments before their cITP diagnosis, with a more marked risk for candidiasis and viral infections. The findings indicate that infection is not only related to the immunomodulation treatment but also to the disease itself.

Use of antidepressants and association with elective termination of pregnancy: population based case-control study.

OBJECTIVE: To assess whether the use of selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, mirtazapine, venlafaxine or other antidepressants is associated with late elective termination of pregnancy. DESIGN: Case-control study using data from national registers. SETTING: Denmark, Finland, and Norway during the period 1996-2007. POPULATION: A total of 14,902 women were included as cases and 148,929 women were included as controls. METHODS: Cases were women with elective termination of pregnancy at 12-23 weeks of gestation. Controls continued their pregnancy and were matched with cases on key factors. MAIN OUTCOME MEASURES: Association between antidepressant use during pregnancy and elective termination of pregnancy at 12-23 weeks of gestation for fetal anomalies, or for maternal ill health or socio-economic disadvantage. RESULTS: At least one prescription of antidepressants was filled by 3.7% of the cases and 2.2% of the controls. Use of any type of antidepressant was associated with elective termination of pregnancy for maternal ill health or socio-economic disadvantage (odds ratio, OR 2.3; 95% confidence interval, 95% CI 2.0-2.5). Elective termination of pregnancy for fetal anomalies was associated with the use of mirtazapine (OR 2.2, 95% CI 1.1-4.5). There was no association between the use of any of the other antidepressants and elective termination of pregnancy for fetal anomalies. CONCLUSION: The use of any type of antidepressants was associated with elective termination of pregnancy at 12-23 weeks for maternal ill health or socio-economic disadvantage, but not with terminations for fetal anomalies. Further studies need to confirm the findings concerning mirtazapine and termination of pregnancy for fetal anomalies.

Higher mortality after myocardial infarction in patients with severe mental illness: a nationwide cohort study.

OBJECTIVES: The aim of this study was to explore the impact of severe mental illness (SMI) on myocardial infarction survival and determine the influence of risk factor burden, myocardial infarction severity and different treatments. DESIGN, SETTING AND PARTICIPANTS: This population-based cohort study, conducted in Sweden during the period 1997-2010, included all patients with a first diagnosis of myocardial infarction in the Swedish nationwide myocardial infarction register SWEDEHEART (n = 209 592). Exposure was defined as a diagnosis of SMI (i.e. bipolar disorder or schizophrenia) in the national patient register prior to infarction. Bias-minimized logistic regression models were identified using directed acyclic graphs and included covariates age, gender, smoking, diabetes, previous cardiovascular disease, myocardial infarction characteristics and treatment. MAIN OUTCOME MEASURES: The outcomes were 30-day and 1-year mortality, obtained through linkage with national population registers. RESULTS: Patients with bipolar disorder (n = 442) and schizophrenia (n = 541) were younger (mean age 68 and 63 years, respectively) than those without SMI (n = 208 609; mean age 71 years). The overall 30-day and 1-year mortality rates were 10% and 18%, respectively. Compared with patients without SMI, patients with SMI had higher 30-day [odds ratio (OR) 1.99, 95% confidence interval (CI) 1.55-2.56] and 1-year mortality (OR 2.11, 95% CI 1.74-2.56) in the fully adjusted model. The highest mortality was observed amongst patients with schizophrenia (30-day mortality: OR 2.58, 95% CI 1.88-3.54; 1-year mortality: OR 2.55, 95% CI 1.98-3.29). CONCLUSION: SMI is associated with a markedly higher mortality after myocardial infarction, also after accounting for contributing factors. It is imperative to identify the reasons for this higher mortality.

Predicting venous thrombosis in women using a combination of genetic markers and clinical risk factors.

BACKGROUND: Family history of venous thromboembolism (VTE) has been suggested to be more useful in risk assessment than thrombophilia testing. OBJECTIVES: We investigated established genetic susceptibility variants for association with VTE and evaluated a genetic risk score in isolation and combined with known trigger factors, including family history of VTE. PATIENTS/METHOD: A total of 18 single nucleotide polymorphisms (SNPs) selected from the literature were genotyped in 2835 women participating in a Swedish nationwide case-control study (the ThromboEmbolism Hormone Study [TEHS]). Association with VTE was assessed by odds ratios (ORs) with 95% confidence interval (CI) using logistic regression. Clinical and genetic predictors that contributed significantly to the fit of the logistic regression model were included in the prediction models. SNP-SNP interactions were investigated and incorporated into the models if found significant. Risk scores were evaluated by calculating the area under the receiver-operating characteristics curve (AUC). RESULTS: Seven SNPs (F5 rs6025, F2 rs1799963, ABO rs514659, FGG rs2066865, F11 rs2289252, PROC rs1799810 and KNG1 rs710446) with four SNP-SNP interactions contributed to the genetic risk score for VTE, with an AUC of 0.66 (95% CI, 0.64-0.68). After adding clinical risk factors, which included family history of VTE, the AUC reached 0.84 (95% CI, 0.82-0.85). The goodness of fit of the genetic and combined scores improved when significant SNP-SNP interaction terms were included. CONCLUSION: Prediction of VTE in high-risk individuals was more accurate when a combination of clinical and genetic predictors with SNP-SNP interactions was included in a risk score.

The influence of comorbidity on mortality in ovarian cancer patients.

BACKGROUND: Ovarian cancer is a severe disease with a peak incidence in the older age groups where concurrent morbidity is common and could potentially influence mortality rates. OBJECTIVES: The aim was to study the influence of common comorbidity diagnoses on mortality in ovarian cancer patients. METHODS: The study population was patients with ovarian cancer in Sweden 1993-2006 (n=11.139) identified in the national Cancer Register. Comorbidity data was obtained from the Patient Register and mortality from Cause of Death Register. Mortality was analyzed with Cox' proportional hazards models and subgroup analyses were performed by age and tumor histology. RESULTS: Almost all of the assessed comorbidities increased mortality in ovarian cancer patients. Thromboembolism was the most hazardous comorbidity (HR=1.95, <1 year after cancer diagnosis and HR=7.83, 1-5 years after cancer diagnosis) followed by hematologic complications (HR=1.84 and 7.11 respectively) and infectious disease (HR=1.48 and 5.28 respectively). The occurrence of diabetes mellitus and hypertension had less impact on mortality. CONCLUSION: Thromboembolism, hematologic complications and infections had a pronounced effect on mortality rates in women with ovarian cancer. The impact of comorbidity was mainly apparent among those with a more prosperous prognosis, such as longer time since cancer diagnosis, less aggressive tumors and younger age.

Pregabalin is increasingly prescribed for neuropathic pain, generalised anxiety disorder and epilepsy but many patients discontinue treatment.

AIM: To assess prescribing patterns, sociodemographic characteristics and previous disease history in patients receiving pregabalin. METHODS: An observational study using register data on dispensed drugs and recorded diagnoses for all patients in Stockholm, Sweden, who filled at least one prescription of pregabalin between July 2005 and December 2009. Analyses focused on prevalence, incidence, diagnosis patterns, prior dispensing of other analgesics/psychotropics and persistence to treatment over time. RESULT: A total of 18,626 patients (mean age 55 years, 63% women) were initiated on treatment between July 2006 and December 2009. Approved indications were recorded in hospital and/or primary care within 1 year prior to the first dispensing for 40% of the patients (epilepsy 1.3%, neuropathic pain 35.5% and generalised anxiety disorder (GAD) 3.6%). Antidepressants were used by 55%, opioids by 49% and sedatives by 48% prior to initiation of pregabalin. One-third (34%) only purchased one prescription and the proportion purchasing pregabalin 1 year after initiation was 42.1% for epilepsy, 36.3% for GAD, 21.5% for neuropathic pain and 25.6% for those without any of the included diagnoses. CONCLUSION: Pregabalin was mainly used as a second-line drug for the treatment of GAD or neuropathic pain and to a lesser extent as add-on therapy in epilepsy. However, a large proportion of all patients only purchased one prescription and the persistence declined rapidly over time. The issue of potential off-label prescribing or poor registration of diagnoses should also be noted as a high proportion had been prescribed the drug without a record of any of the approved indications.

The Nordic prescription databases as a resource for pharmacoepidemiological research--a literature review.

PURPOSE: All five Nordic countries have nationwide prescription databases covering all dispensed drugs, with potential for linkage to outcomes. The aim of this review is to present an overview of therapeutic areas studied and methods applied in pharmacoepidemiologic studies using data from these databases. METHODS: The study consists of a Medline-based structured literature review of scientific papers published during 2005-2010 using data from the prescription databases in Denmark, Finland, Iceland, Norway, and Sweden, covering 25 million inhabitants. Relevant studies were analyzed in terms of pharmacological group, study population, outcomes examined, type of study (drug utilization vs. effect of drug therapy), country of origin, and extent of cross-national collaboration. RESULTS: A total of 515 studies were identified. Of these, 262 were conducted in Denmark, 97 in Finland, 4 in Iceland, 87 in Norway, and 61 in Sweden. Four studies used data from more than one Nordic country. The most commonly studied drugs were those acting on the nervous system, followed by cardiovascular drugs and gastrointestinal/endocrine drugs. A total of 228 studies examined drug utilization and 263 focused on the effects and safety of drug therapy. Pregnant women were the most commonly studied population in safety studies, whereas prescribers' adherence to guidelines was the most frequent topic of drug utilization studies. CONCLUSIONS: The Nordic prescription databases, with their possibility of record-linkage, represent an outstanding resource for assessing the beneficial and adverse effects of drug use in large populations, under routine care conditions, and with the potential for long-term follow-up.

Evaluation of prevalent and incident ovarian cancer co-morbidity.

BACKGROUND: The peak in incidence of ovarian cancer occurs around 65 years and concurrent increasing risk by age for a number of diseases strongly influence treatment and prognosis. The aim was to explore prevalence and incidence of co-morbidity in ovarian cancer patients compared with the general population. METHODS: The study population was patients with ovarian cancer in Sweden 1993-2006 (n=11 139) and five controls per case (n=55 687). Co-morbidity from 1987 to 2006 was obtained from the Swedish Patient Register. Prevalent data were analysed with logistic regression and incident data with Cox proportional hazards models. RESULTS: Women developing ovarian cancer did not have higher overall morbidity than other women earlier than 3 months preceding cancer diagnosis. However, at time of diagnosis 11 of 13 prevalent diagnosis groups were more common among ovarian cancer patients compared with controls. The incidence of many common diagnoses was increased several years following the ovarian cancer and the most common diagnoses during the follow-up period were thromboembolism, haematologic and gastrointestinal complications. CONCLUSION: Women developing ovarian cancer do not have higher overall morbidity the years preceding cancer diagnosis. The incidence of many common diagnoses was increased several years following the ovarian cancer. It is crucial to consider time between co-morbidity and cancer diagnosis to understand and interpret associations.

Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide prevalence study.

OBJECTIVES: To examine the prevalence of preterm birth, infants with low Apgar score, small for gestational age (SGA) birth, stillbirth and congenital abnormalities in women with rheumatoid arthritis (RA) compared with women without RA. DESIGN: Prevalence study. SETTING: Combined Sweden and Denmark nationwide from 1994 to 2006. SUBJECTS: We included 871,579 women with a first-time singleton birth identified through population-based healthcare databases. MAIN OUTCOME MEASURES: We compared the prevalence of preterm birth, low Apgar score (<7 at 5 min), SGA birth, stillbirth and congenital abnormalities amongst women with RA compared with women without RA using prevalence odds ratio (OR) with 95% confidence interval (95% CI), whilst controlling for maternal age, smoking, parental cohabitation and year. We stratified analyses by period of birth (1994-1997, 1998-2001 and 2002-2006). RESULTS: Amongst 1199 women with RA, 7.8% gave birth between 32 and 36 gestational weeks (adjusted OR, 1.44; 95% CI, 1.14-1.82), 1.4% gave birth before gestational week 32 (adjusted OR, 1.55; 95% CI, 0.97-2.47), 1.6% had an infant with a low Apgar score (OR, 0.99; 95% CI, 0.95-1.65), 5.9% had an SGA birth (adjusted OR, 1.56; 95% CI, 1.2-2.01), 0.9% experienced stillbirth (adjusted OR, 2.07; 95% CI, 0.98-4.35) and 4.3% gave birth to an infant with congenital abnormalities (adjusted OR,1.32; 95% CI, 0.98-1.79). The OR for congenital abnormalities decreased from 2.57 (95% CI, 1.59-4.16) in 1994-1997 to 1.00 (95% CI, 0.64-1.56) in 2002-2006. CONCLUSIONS: Women with RA had a high prevalence of most adverse birth outcomes. This could be due to inflammatory activity, medical treatment or other factors not controlled for.

Effect of Swedish snuff (snus) on preterm birth.

OBJECTIVE: To compare the effects of Swedish snuff and cigarette smoking on risks of preterm birth. DESIGN: Population-based cohort study. SETTING: Sweden. POPULATION: All live, singleton births in Sweden 1999-2006. METHODS: Odds ratios (OR) with 95% confidence intervals (CI) were used to estimate relative risks for preterm birth in snuff users (n = 7607), light smokers (1-9 cigarettes/day; n = 41 436) and heavy smokers (ten or more cigarettes/day; n = 16 951) using non-tobacco users (n = 503 957) as reference. MAIN OUTCOME MEASURES: Very (<32 weeks) and moderately (32-36 weeks) preterm birth. RESULTS: Compared with non-tobacco users, snuff users had increased risks of both very (adjusted OR 1.38; 95% CI 1.04-1.83) and moderately (adjusted OR 1.25; 95% CI 1.12-1.40) preterm birth. Compared with non-tobacco users, light smokers had increased risks of both very (adjusted OR 1.60; 95% CI 1.42-1.81) and moderately (adjusted OR: 1.18; 95% CI: 1.12-1.24) preterm birth, and heavy smokers had even higher risks. Among smokers, but not among snuff users, the risk was more pronounced for spontaneous than induced preterm birth. CONCLUSIONS: The use of Swedish snuff was associated with increased risks of very and moderately preterm birth with both spontaneous and induced onsets. Swedish snuff is not a safe alternative to cigarette smoking during pregnancy.

Prenatal ultrasound exposure and children's school performance at age 15-16: follow-up of a randomized controlled trial.

OBJECTIVE: To evaluate the association between prenatal ultrasound exposure and school performance at 15-16 years of age. METHODS: The study population consisted of children born to women who participated in a randomized controlled trial on the second-trimester ultrasound examination in Sweden from 1985 to 1987. Information about the children's grades when graduating from primary school and information on socioeconomic factors was obtained from Swedish nationwide registers. Comparisons were made using linear and logistic regression analyses according to randomization to ultrasound, ultrasound exposure in the second trimester and ultrasound exposure at any time during pregnancy. Boys and girls were analyzed separately. RESULTS: Of the 4756 singleton children from the randomized trial, we identified 4458 (94%) in the National School Register. There were no statistically significant differences in school performance for boys or girls according to randomization or exposure to ultrasound in the second trimester. Compared to those who were unexposed, boys exposed to ultrasound at least once at any time during fetal life had a tendency towards lower mean school grades in general (-4.39 points; 95% CI, -9.59 to 0.81 (max possible, 320) points) and in physical education (-0.45 points; 95% CI, -0.91 to 0.01 (max possible, 20) points), but the differences did not reach significance. CONCLUSION: In general, routine ultrasound examination in the second trimester had no effect on overall school performance in teenagers.

Effects of natural childbirth preparation versus standard antenatal education on epidural rates, experience of childbirth and parental stress in mothers and fathers: a randomised controlled multicentre trial.

OBJECTIVE: To examine the effects of antenatal education focussing on natural childbirth preparation with psychoprophylactic training versus standard antenatal education on the use of epidural analgesia, experience of childbirth and parental stress in first-time mothers and fathers. DESIGN: Randomised controlled multicentre trial. SETTING: Fifteen antenatal clinics in Sweden between January 2006 and May 2007. SAMPLE: A total of 1087 nulliparous women and 1064 of their partners. METHODS: Natural group: Antenatal education focussing on natural childbirth preparation with training in breathing and relaxation techniques (psychoprophylaxis). Standard care group: Standard antenatal education focussing on both childbirth and parenthood, without psychoprophylactic training. Both groups: Four 2-hour sessions in groups of 12 participants during third trimester of pregnancy and one follow-up after delivery. MAIN OUTCOME MEASURES: Epidural analgesia during labour, experience of childbirth as measured by the Wijma Delivery Experience Questionnaire (B), and parental stress measured by the Swedish Parenthood Stress Questionnaire. RESULTS: The epidural rate was 52% in both groups. There were no statistically significant differences in the experience of childbirth or parental stress between the randomised groups, either in women or men. Seventy percent of the women in the Natural group reported having used psychoprophylaxis during labour. A minority in the Standard care group (37%) had also used this method, but subgroup analysis where these women were excluded did not change the principal findings. CONCLUSION: Natural childbirth preparation including training in breathing and relaxation did not decrease the use of epidural analgesia during labour, nor did it improve the birth experience or affect parental stress in early parenthood in nulliparous women and men, compared with a standard form of antenatal education.

The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database.

OBJECTIVE: To assess whether use of tranexamic acid is associated with an increased risk of venous thromboembolism (VTE). DESIGN: Nested case-control study. SETTING: Database study using the General Practice Research Database for the years 1992-1998. POPULATION: Women aged 15-49 years with a diagnosis of menorrhagia. METHODS: Multivariate conditional logistic regression was used to estimate the risk for VTE associated with different drug treatments for menorrhagia, adjusting for confounders. MAIN OUTCOME MEASURES: Adjusted odds ratios with 95% CI. RESULTS: A total of 134 cases of VTE and 552 matched controls were identified. Recent use of tranexamic acid was scarce, yielding an adjusted odds ratio for VTE of 3.20 (95% CI 0.65-15.78). The use of mefenamic acid (ORadj 5.54 [95% CI 2.13-14.40]) or norethisterone (ORadj 2.41 [95% CI 1.00-5.78]) was associated with an increased risk of VTE, as was a recent--in relation to menorrhagia--diagnosis of anaemia or a haemoglobin value <11.5 g/dl (ORadj 2.23 [95% CI 1.02-4.86]). CONCLUSIONS: We found that tranexamic acid was associated with an increased risk of VTE, although the risk estimate did not reach statistical significance. Increased risks of VTE associated with other treatments for menorrhagia were observed. The increased risk of VTE observed with a diagnosis of anaemia--a proxy for more severe menorrhagia--suggests that menorrhagia could be a prothrombotic condition. The observed association between VTE, tranexamic acid and other treatments for menorrhagia may thus partly be explained by confounding by indication. The possibility that menorrhagia is itself a risk factor for VTE merits further investigation.

Prenatal ultrasound and the risk of childhood brain tumour and its subtypes.

We carried out a nationwide case-control study of childhood brain tumours in Sweden (n=512) by histological subtype in relation to prenatal ultrasound, extracting data from antenatal records and the Medical Birth Register. We found no increased risk for brain tumour after ultrasound exposure, either for all tumours or for any subgroup.

Prenatal X-ray exposure and childhood brain tumours: a population-based case-control study on tumour subtypes.

We investigated childhood brain tumours by histological subtype in relation to prenatal X-ray among all children, less than 15 years of age, born in Sweden between 1975 and 1984. For each case, one control was randomly selected from the Medical Birth Register, and exposure data on prenatal X-ray were extracted blindly from antenatal medical records. Additional information on maternal reproductive history was obtained from the Medical Birth Register. We found no overall increased risk for childhood brain tumour after prenatal abdominal X-ray exposure (adjusted odds ratio (OR): 1.02, 95% confidence interval (CI): 0.64-1.62); primitive neuroectodermal tumours had the highest risk estimate (OR: 1.88, 95% CI: 0.92-3.83).

Epidemiological studies on adverse effects of prenatal ultrasound--which are the challenges?

A large number of foetuses are scanned on a routine basis and although it is generally assumed that prenatal ultrasound is safe; very few studies have in fact focused on possible adverse effects in humans. The epidemiological tools when studying possible adverse effects of prenatal ultrasound are randomised controlled trials and observational studies such as cohort and case-control studies. There are advantages and disadvantages with all study designs. In this review, some of the challenges that have to be met are discussed based on experiences from a randomised controlled trial, cohort studies and an ongoing case-control study.