Epidemiology of lower limb fractures in general practice in the United Kingdom.

STUDY OBJECTIVE: To estimate the incidence of lower limb fractures in the United Kingdom and assess the relative importance of various risk factors for lower limb fractures. DESIGN: Cohort analysis and matched case-control study. SETTING: General practices contributing information to the General Practice Research Database. SUBJECTS: Individuals registered with these general practices who were at risk for a first time lower limb fracture from 1 January 1990 to 31 December 2001. MAIN OUTCOME MEASURES: Age, sex, and fracture site specific incidence rates; relative risks and population attributable risks for various medical risk factors. RESULTS: Overall, the risk of lower limb fracture was 17% higher in women then in men. Within age groups, men and women had generally similar proportions of fractures at specific sites in the lower limb. Among the risk factors evaluated, road collisions were associated with the highest relative risk for lower limb fracture, but only accounted for 3.1% or less of the population attributable risk for specific fracture types in any age group. The relative risk for lower limb fracture associated with a diagnosis of dementia was 2.3 (95% confidence interval 2.0 to 2.6), while relative risk estimates for other medical diagnoses were less than 2. Fracture risk was increased among current users of corticosteroids, antipsychotics, antidepressants, and hypnotic/sedatives, but the population attributable risks for each of these drug classes within fracture and age specific strata were only 3.0% or less. CONCLUSIONS: Many risk factors for lower limb fracture have been identified, but population attributable risk estimates for various risk factors are small. These findings suggest that multifactorial prevention programs are needed to decrease the incidence of lower limb fractures in the general population.

Statin use and cancer risk in the General Practice Research Database.

In a matched case-control study using the General Practice Research Database, current statin use was not associated with a significantly altered risk of any of 13 studied cancers. Untreated hyperlipidaemia was associated with slightly increased risks of colon cancer (relative risk 1.8; 95% confidence interval 1.2-2.8), prostate cancer (1.5; 1.1-2.0), and bladder cancer (1.9; 1.2-3.1).

The risk of stillbirth in pregnancies before and after the onset of diabetes.

AIMS: There is significant controversy as to whether or not stillbirth is increased in pregnancies prior to the onset of diabetes. An observed increase may be indicative of risks associated with untreated gestational diabetes. It is generally accepted that the risk of stillbirth in pregnancies that occur after the onset of diabetes has been diminished by modern obstetric care. However, the degree of residual risk is not well quantified. This study sought to examine the rates of stillbirth before and after the onset of diabetes compared with the general population. METHODS: Retrospective cohort and nested case-control study. The study population was drawn from the UK-based General Practice Research Database, comprising some 300 practices, with data collection from the late 1980s until September 1999. From the base population, 913 diabetic women who had had a pregnancy were identified and 10,000 subjects without diabetes were randomly chosen as controls. Stillbirth was defined as death in utero after 20 weeks or with birth weight >500 g. RESULTS: The stillbirth rates were higher in prediabetic pregnancies (19.7/1000), and in those occurring after the diagnosis of diabetes (33.7/1000), compared with the non-diabetic population (5.5/1000). Stillbirths were matched to four live births by maternal age and year of birth. Prediabetic pregnancy and pregnancy after the onset of diabetes were strongly associated with stillbirth: odds ratio (OR)=4.68 (1.67, 13.08) and OR=4.39 (2.22, 8.64), respectively. CONCLUSIONS: The risk of stillbirth was increased in both prediabetic and post-diabetic pregnancy.

Statin use, hyperlipidaemia, and the risk of breast cancer.

Hydroxymethyl glutaryl coenzyme A inhibitors ("statins") are carcinogenic in rodents and an increased incidence of breast cancer was reported among pravastatin users in one randomised trial. We conducted a case-control study in the General Practice Research Database to evaluate the risk of breast cancer among 50- to 79-year old women treated with statins for hyperlipidaemia. Case and control women were matched by age, general practice, duration of prescription history in the General Practice Research Database, and index date. Adjusting for history of benign breast disease, body mass index, and use of hormone replacement therapy, women currently treated with statins had an estimated relative risk for breast cancer of 1.0 (95% confidence interval 0.6-1.6) compared to women without hyperlipidaemia. Untreated hyperlipidaemia was associated with an increased risk of breast cancer (estimated relative risk 1.6; 95% confidence interval 1.1-2.5). The estimated relative risk among women currently receiving only non-statin lipid-lowering drugs was similar to that of women with untreated hyperlipidaemia (1.8; 95% confidence interval 0.9-3.4). We found no evidence for an increasing trend in breast cancer risk with increasing duration of statin use (median duration 1.8 years, maximum 8.6 years).

Risk of venous thromboembolism with cyproterone or levonorgestrel contraceptives.

Results of studies have shown that there is an excess risk of venous thromboembolism in users of oral contraceptives containing cyproterone compared with those containing levonorgestrel. We did a case-control study, in which we assessed the risk of idiopathic venous thromboembolism in women taking combined low-dose oestrogen oral contraceptives containing cyproterone (n=24401) or levonorgestrel (n=75000). We compared the 26 women in this population who had idiopathic venous thromboembolism with 144 matched controls. 12 individuals and 30 controls were taking contraceptives that contained cyproterone. Our results suggest that risk of venous thromboembolism is increased four-fold in women taking contraceptives containing cyproterone by comparison with those exposed to levonorgestrel.

Acetaminophen and the risk of renal and bladder cancer in the general practice research database.

We conducted a nested, matched case-control study in the General Practice Research Database (GPRD) to assess whether acetaminophen use is associated with renal or bladder cancer. We matched 109 cases of renal cancer and 189 cases of bladder cancer with up to 4 controls each by age, sex, general practice, duration of drug history in the GPRD, and index date. We found that use of acetaminophen from 1 to 5 years before the index date was associated with an increased risk of renal cancer, with a direct relation between risk and number of prescriptions and an adjusted odds ratio of 2.3 (95% CI 1.0-5.3) for subjects with 20 or more prescriptions. There was no evidence for an increase in risk of bladder cancer with acetaminophen use. We found no association between use of non-steroidal anti-inflammatory drugs and either renal or bladder cancer. These results support previous findings from our group and are consistent with a slight increase in the risk of renal cancer, but not bladder cancer, with heavy acetaminophen use.

Live attenuated polio vaccine and the risk of intussusception.

AIMS: Since suspicion has been raised that administration of an oral live attenuated rotavirus vaccine may increase the risk of intussusception in young children, there has been concern about the possible effects of oral polio vaccine. The aim of the study was to evaluate the relationship between oral attenuated polio vaccine and intussusception in children below the age of 1 year. METHODS: We conducted a nested case-control analysis based on data from the General Practice Research Database which encompassed 133 children who developed documented intussusception during the first year of life and 515 controls. RESULTS: The time from oral polio vaccine to the index date was similar in cases and controls. Relative risk estimates for intussusception ranged from 0.7 (95% CI 0.2, 2.1) for babies whose last oral polio vaccine was given 29-35 days before their index date to 1.0 (95% CI 0.4, 2.3) for those whose last oral polio vaccine was given 15-21 days before their index date (compared with babies vaccinated more than 43 days before their index date). CONCLUSIONS: There is no suggestion that oral polio vaccine increases the risk for intussusception.

Risk of cataract in patients treated with statins.

BACKGROUND: Studies in dogs showed that some hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) are associated with cataract when administered in excessive doses. Clinical safety data of statins regarding cataract development in humans have been of limited value so far. OBJECTIVE: To determine whether long-term use of statins is associated with an increased risk of cataract. METHODS: We conducted a case-control analysis using data from the United Kingdom-based General Practice Research Database. The main outcome was a first-time diagnosis of cataract and/or cataract extraction in patients aged 40 to 79 years. Controls were matched to cases on age, sex, practice, calendar time, and duration of medical history in the database. Use of statins, fibrates, or other lipid-lowering drugs was compared with nonuse of any lipid-lowering drug, stratified by exposure duration and dose. RESULTS: We identified 7405 cases and 28 327 controls. Long-term use of statins (eg, > or =30 prescriptions) was not associated with an increased cataract risk (adjusted odds ratio [OR], 0.9; 95% confidence interval [CI], 0.5-1.6), nor was use of fibrates or of other lipid-lowering drugs (adjusted OR, 0.5; 95% CI, 0.3-1.1; and OR, 0.7; 95% CI, 0.1-5.6, respectively). We found evidence that concomitant use of simvastatin and erythromycin, a potent inhibitor of simvastatin metabolism, is associated with an increased cataract risk (adjusted odds ratio, 2.2; 95% confidence interval, 1.2-4.1). CONCLUSIONS: Our study provides evidence that long-term use of therapeutic statin doses does not increase the risk of developing cataract. Concomitant use of erythromycin and simvastatin may increase the cataract risk.

Use of selective serotonin reuptake inhibitors and risk of developing first-time acute myocardial infarction.

AIMS: Selective serotonin reuptake inhibitors (SSRIs) have been associated with serotonin depletion in platelets, potentially leading to abnormal aggregation and prolonged bleeding time. In view of the importance of serotonin in coronary thrombosis, and decreased platelet serotonin concentrations associated with SSRIs, the present study was performed to test the hypothesis of a decreased risk of acute myocardial infarction (AMI) associated with SSRIs. METHODS: We conducted a population-based case-control analysis using the UK General Practice Research Database (GPRD). A total of 3319 patients aged 75 years or younger free of clinical conditions predisposing to ischaemic heart disease, with a first-time diagnosis of AMI between 1992 and 1997, and 13 139 controls without AMI matched to cases for age, sex, general practice attended, and calendar time were included. Conditional logistic regression was used to estimate relative risks. RESULTS: Adjusted odds ratios (with 95% CI) for current use of SSRIs, non-SSRIs, or other antidepressants, compared to the group of nonusers of antidepressants were 0.9 (95% CI 0.5,1.8), 0.9 (95% CI 0.7,1.2), and 1.3 (95% CI 0.6,2.8), respectively. As compared with nonuse of SSRIs, current use (regardless of any other antidepressants used) resulted in an adjusted OR of 1.1 (95% CI 0.7,1.6). CONCLUSIONS: The current analysis provides evidence that SSRI exposure does not substantially decrease the risk of developing first-time AMI in patients free of factors predisposing to ischaemic heart disease. However, due to relatively small numbers of exposed subjects and the resulting wide confidence intervals, further studies may be needed to document a lack of effect of SSRIs in subjects without pre-existing diseases predisposing to AMI.

Postmenopausal estrogen replacement therapy and the risk of Alzheimer disease.

BACKGROUND: Previous studies have examined the relation between postmenopausal estrogen replacement therapy (ERT) and the risk of Alzheimer disease (AD). The findings have been inconsistent, since some studies have been interpreted as showing a protective effect while others have reported no effect. OBJECTIVE: To determine whether exposure to ERT is associated with a reduced risk of AD. DESIGN: Population-based nested case-control study. SETTING: The United Kingdom-based General Practice Research Database. PATIENTS: The base cohort consisted of women who were recipients of ERT (n = 112 481) and a similar cohort of women who did not use estrogens (n = 108 925). The 2 cohorts were restricted to women born on or before January 1, 1950. From the 2 cohorts, we identified and verified 59 newly diagnosed cases of AD and 221 matched control subjects. MAIN OUTCOME MEASURE: Prior and current use of ERT in cases compared with controls. RESULTS: Among the 59 newly diagnosed cases of AD, 15 (25%) were current estrogen users, while among the controls, 53 (24%) were current users. The adjusted odds ratio comparing all current estrogen recipients with nonrecipients was 1.18 (95% confidence interval, 0.59-2.37). In estrogen users who took the drug for 5 years or longer compared with nonusers, the odds ratio was 1.05 (95% confidence interval, 0.32-3.44). Odds ratios were similar for estrogen recipients who received estrogens alone and recipients who received combined estrogen-progestin treatment. CONCLUSION: The use of ERT in women after the onset of menopause was not associated with a reduced risk of developing AD.

Mumps, measles, and rubella vaccine and the incidence of autism recorded by general practitioners: a time trend analysis.

OBJECTIVE: To estimate changes in the risk of autism and assess the relation of autism to the mumps, measles, and rubella (MMR) vaccine. DESIGN: Time trend analysis of data from the UK general practice research database (GPRD). SETTING: General practices in the United Kingdom. SUBJECTS: Children aged 12 years or younger diagnosed with autism 1988-99, with further analysis of boys aged 2 to 5 years born 1988-93. MAIN OUTCOME MEASURES: Annual and age specific incidence for first recorded diagnoses of autism (that is, when the diagnosis of autism was first recorded) in the children aged 12 years or younger; annual, birth cohort specific risk of autism diagnosed in the 2 to 5 year old boys; coverage (prevalence) of MMR vaccination in the same birth cohorts. RESULTS: The incidence of newly diagnosed autism increased sevenfold, from 0.3 per 10 000 person years in 1988 to 2.1 per 10 000 person years in 1999. The peak incidence was among 3 and 4 year olds, and 83% (254/305) of cases were boys. In an annual birth cohort analysis of 114 boys born in 1988-93, the risk of autism in 2 to 5 year old boys increased nearly fourfold over time, from 8 (95% confidence interval 4 to 14) per 10 000 for boys born in 1988 to 29 (20 to 43) per 10 000 for boys born in 1993. For the same annual birth cohorts the prevalence of MMR vaccination was over 95%. CONCLUSIONS: Because the incidence of autism among 2 to 5 year olds increased markedly among boys born in each year separately from 1988 to 1993 while MMR vaccine coverage was over 95% for successive annual birth cohorts, the data provide evidence that no correlation exists between the prevalence of MMR vaccination and the rapid increase in the risk of autism over time. The explanation for the marked increase in risk of the diagnosis of autism in the past decade remains uncertain.

Hyperemesis gravidarum and the sex of the offspring.

Studies have suggested that offspring of women hospitalized for hyperemesis gravidarum have a different sex ratio than those of women without this diagnosis, but little is known of the potential association between fetal gender and variables such as severity of hyperemesis, gestational trimester, and maternal age. Our findings provide evidence that pregnant women with a diagnosis of hyperemesis gravidarum in the first trimester give birth to a higher proportion of female newborns than do all mothers, regardless of whether they are hospitalized.

Statins and the risk of dementia.

BACKGROUND: Dementia affects an estimated 10% of the population older than 65 years. Because vascular and lipid-related mechanisms are thought to have a role in the pathogenesis of Alzheimer's disease and vascular dementia, we did an epidemiological study of the potential effect of HMGCoA (3 hydroxy-3methylglutaryl-coenzyme A) reductase inhibitors (statins) and other lipid-lowering agents on dementia. METHODS: We used a nested case-control design with information derived from 368 practices which contribute to the UK-based General Practice Research Database. The base study population included three groups of patients age 50 years and older: all individuals who had received lipid-lowering agents (LLAs); all individuals with a clinical diagnosis of untreated hyperlipidaemia; and a randomly selected group of other individuals. From this base population, all cases with a computer-recorded clinical diagnosis of dementia were identified. Each case was matched with up to four controls derived from the base population on age, sex, practice, and index date of case. FINDINGS: The study encompassed 284 cases with dementia and 1080 controls. Among controls 13% had untreated hyperlipidaemia, 11% were prescribed statins, 7% other LLAs, and 69% had no hyperlipidaemia or LLA exposure. The relative risk estimates of dementia adjusted for age, sex, history of coronary-artery disease, hypertension, coronary-bypass surgery and cerebral ischaemia, smoking and body mass index for individuals with untreated hyperlipidaemia (odds ratio 0.72 [95% CI 0.45-1.14]), or treated with nonstatin LLAs (0.96 [0.47-1.97], was close to 1.0 and not significant compared with people who had no diagnosis of hyperlipidaemia or exposure to other lipid-lowering drugs. The adjusted relative risk for those prescribed statins was 0.29 (0.13-0.63; p=0.002). INTERPRETATION: Individuals of 50 years and older who were prescribed statins had a substantially lowered risk of developing dementia, independent of the presence or absence of untreated hyperlipidaemia, or exposure to nonstatin LLAs. The available data do not distinguish between Alzheimer's disease and other forms of dementia.

Antipsychotic drug use and risk of first-time idiopathic venous thromboembolism: a case-control study.

BACKGROUND: Antipsychotic drugs have been associated with an increased risk of adverse events such as venous thromboembolism. Our aim was to assess this risk in users of conventional antipsychotic drugs who had been diagnosed with first-time, idiopathic venous thromboembolism. METHODS: From a baseline population of 29,952 recipients of conventional and atypical antipsychotic drugs aged younger than 60 years, we identified 42 individuals with idiopathic venous thromboembolism and 172 matched controls. We compared risk of current and recent use of antipsychotic drugs with non-use before the index date in cases and controls. FINDINGS: Current exposure to conventional antipsychotic drugs was associated with a significantly increased risk of idiopathic venous thromboembolism compared with non-use (adjusted odds ratio 7.1 [95% CI 2.3-21.97]). Although we found no difference between phenothiazines, thioxanthenes, or other conventional antipsychotic drugs, low potency antipsychotic drugs drugs such as chlorpromazine and thioridazine were more strongly associated with venous thromboembolism (odds ratio 24.1 [3.3-172.7]) than were high potency antipsychotic drugs such as haloperidol (3.3 [0.8-13.2]). The risk for venous thrombosis was highest during the first few months of conventional antipsychotic drug use. INTERPRETATION: Current exposure to conventional antipsychotic drugs significantly increases the risk of idiopathic venous thromboembolism in men and women younger than 60 years of age.

The incidence of breast cancer in the General Practice Research Database compared with national cancer registration data.

Breast cancer incidence rates in the UK from 1990 to 1996 among women aged 35-69 estimated from the General Practice Research Database (GPRD) were closely similar to those reported by the Office for National Statistics from cancer registration data (ONS). The GPRD is a valuable and up-to-date resource for further study of the incidence of breast cancer in the UK as well as changes in cancer treatment and their relation to survival trends.

Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis.

OBJECTIVE: To compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel. DESIGN: Cohort and case-control analyses derived from the General Practice Research Database. SETTING: UK general practices, January 1993 to December 1999. PARTICIPANTS: Women aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel. MAIN OUTCOME MEASURES: Relative incidence (cohort study) and odds ratios (case-control study) as measures of the relative risk of venous thromboembolism. RESULTS: The adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged. CONCLUSIONS: These findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.

Intracranial haemorrhage and use of selective serotonin reuptake inhibitors.

AIMS: In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs. METHODS: We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression. RESULTS: We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10. 8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0. 8 (0.3,2.3). The estimate for 'other antidepressants' was 0.7 (0.3,1. 6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid). CONCLUSIONS: Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.

HMG-CoA reductase inhibitors and the risk of fractures.

CONTEXT: Recent animal studies have suggested that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) increase bone formation, volume, and density. It is unknown whether use of statins is associated with a decreased risk of fractures in humans. OBJECTIVE: To determine whether exposure to statins, fibrates, or other lipid-lowering drugs is associated with reduced bone fracture risk. DESIGN: Population-based, nested case-control analysis. SETTING: The UK-based General Practice Research Database (GPRD), comprising some 300 practices, with data collection from the late 1980s until September 1998. SUBJECTS: Within a base population of 91,611 individuals aged at least 50 years (28,340 individuals taking lipid-lowering drugs, 13,271 untreated individuals with a diagnosis of hyperlipidemia, and 50,000 randomly selected individuals without diagnosis of hyperlipidemia), we identified 3940 case patients who had a bone fracture and 23,379 control patients matched for age (+/-5 years), sex, general practice attended, calendar year, and years since enrollment in the GPRD. MAIN OUTCOME MEASURES: Use of statins, fibrates, or other lipid-lowering drugs in case patients vs control patients. RESULTS: After controlling for body mass index, smoking, number of physician visits, and corticosteroid and estrogen use, current use of statins was associated with a significantly reduced fracture risk (adjusted odds ratio [OR], 0.55; 95% confidence interval [CI], 0.44-0.69) compared with nonuse of lipid-lowering drugs. Current use of fibrates or other lipid-lowering drugs was not related to a significantly decreased bone fracture risk (adjusted OR, 0.87; 95% CI, 0.70-1.08 and adjusted OR, 0.76; 95% CI, 0.41-1.39, respectively). CONCLUSIONS: This study suggests that current exposure to statins is associated with a decreased risk of bone fractures in individuals age 50 years and older. This finding has a potentially important public health impact and should be confirmed further in controlled prospective trials. JAMA. 2000;283:3205-3210