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1.  Hospital admissions in relation to body mass index in UK women: a prospective cohort study 
BMC Medicine  2014;12:45.
Background
Adiposity is associated with many adverse health outcomes but little direct evidence exists about its impact on the use of health care services. We aim to describe the relationship between body mass index (BMI) and rates of hospital admission in middle-aged UK women.
Methods
Among 1,251,619 Million Women Study participants, 50- to 64-years old at entry into the study, routine data on hospital admissions were used to estimate hospitalization rates according to BMI after standardization for age, region of recruitment, socioeconomic status, reproductive history, smoking status, hormonal therapy use and alcohol intake. Proportional hazards models were used to estimate adjusted relative risks of hospitalization separately for 25 common types of admission.
Results
During an average of 9.2 years follow-up, there were 2,834,016 incident hospital admissions. In women with BMIs (in kg/m2) of <22.5, 22.5 to <25, 25 to <30, 30 to <35 and 35+ standardized admission rates (and 95% confidence intervals (CIs)) per woman over a 10-year period were 2.4 (2.4 to 2.4), 2.4 (2.3 to 2.4), 2.6 (2.6 to 2.6), 3.0 (3.0 to 3.0) and 3.5 (3.4 to 3.5), respectively (P-value for heterogeneity <0.001). The relative increase in admission rates per 5 kg/m2 increase in BMI was 1.12 (1.12 to 1.13). This relationship did not vary materially by age. Corresponding average durations of stay (in days) per hospital visit within the same categories of BMI were: 3.1 (3.1 to 3.2), 2.8 (2.7 to 2.8), 2.9 (2.9 to 2.9), 3.2 (3.1 to 3.2) and 3.8 (3.7 to 3.8), respectively (P <0.001).
Significant increases in the risk of admission with increasing BMI were observed for 19 of the 25 types of hospital admission considered. BMI was most strongly associated with admissions with diabetes, knee-replacement, gallbladder disease and venous thromboembolism, but marked associations were found with many other common categories of admission including cataracts, carpal tunnel syndrome and diverticulitis.
Conclusions
Among women 50- to 84-years old in England, around one in eight hospital admissions are likely to be attributable to overweight or obesity, translating to around 420,000 extra hospital admissions and two million extra days spent in hospital, annually.
doi:10.1186/1741-7015-12-45
PMCID: PMC4003825  PMID: 24629170
Body mass index; Obesity; Hospital admissions; Health services; Attributable risk; Cohort study
2.  Body mass index and incident coronary heart disease in women: a population-based prospective study 
BMC Medicine  2013;11:87.
Background
A high body mass index (BMI) is associated with an increased risk of mortality from coronary heart disease (CHD); however, a low BMI may also be associated with an increased mortality risk. There is limited information on the relation of incident CHD risk across a wide range of BMI, particularly in women. We examined the relation between BMI and incident CHD overall and across different risk factors of the disease in the Million Women Study.
Methods
1.2 million women (mean age = 56 years) participants without heart disease, stroke, or cancer (except non-melanoma skin cancer) at baseline (1996 to 2001) were followed prospectively for 9 years on average. Adjusted relative risks and 20-year cumulative incidence from age 55 to 74 years were calculated for CHD using Cox regression.
Results
After excluding the first 4 years of follow-up, we found that 32,465 women had a first coronary event (hospitalization or death) during follow-up. The adjusted relative risk for incident CHD per 5 kg/m2 increase in BMI was 1.23 (95% confidence interval (CI) 1.22 to 1.25). The cumulative incidence of CHD from age 55 to 74 years increased progressively with BMI, from 1 in 11 (95% CI 1 in10 to 12) for BMI of 20 kg/m2, to 1 in 6(95% CI 1 in 5 to 7) for BMI of 34 kg/m2. A 10 kg/m2 increase in BMI conferred a similar risk to a 5-year increment in chronological age. The 20 year cumulative incidence increased with BMI in smokers and non-smokers, alcohol drinkers and non-drinkers, physically active and inactive, and in the upper and lower socioeconomic classes. In contrast to incident disease, the relation between BMI and CHD mortality (n = 2,431) was J-shaped. For the less than 20 kg/m2 and ≥35 kg/m2 BMI categories, the respective relative risks were 1.27 (95% CI 1.06 to 1.53) and 2.84 (95% CI 2.51 to 3.21) for CHD deaths, and 0.89 (95% CI 0.83 to 0.94) and 1.85 (95% CI 1.78 to 1.92) for incident CHD.
Conclusions
CHD incidence in women increases progressively with BMI, an association consistently seen in different subgroups. The shape of the relation with BMI differs for incident and fatal disease.
doi:10.1186/1741-7015-11-87
PMCID: PMC3661394  PMID: 23547896
obesity; body mass index; coronary heart disease; incidence; mortality; women
3.  The 21st century hazards of smoking and benefits of stopping: a prospective study of one million women in the UK 
Lancet  2013;381(9861):133-141.
Summary
Background
Women born around 1940 in countries such as the UK and USA were the first generation in which many smoked substantial numbers of cigarettes throughout adult life. Hence, only in the 21st century can we observe directly the full effects of prolonged smoking, and of prolonged cessation, on mortality among women in the UK.
Methods
For this prospective study, 1·3 million UK women were recruited in 1996–2001 and resurveyed postally about 3 and 8 years later. All were followed to Jan 1, 2011, through national mortality records (mean 12 woman-years, SD 2). Participants were asked at entry whether they were current or ex-smokers, and how many cigarettes they currently smoked. Those who were ex-smokers at both entry and the 3-year resurvey and had stopped before the age of 55 years were categorised by the age they had stopped smoking. We used Cox regression models to obtain adjusted relative risks that compared categories of smokers or ex-smokers with otherwise similar never-smokers.
Findings
After excluding 0·1 million women with previous disease, 1·2 million women remained, with median birth year 1943 (IQR 1938–46) and age 55 years (IQR 52–60). Overall, 6% (66 489/1 180 652) died, at mean age 65 years (SD 6). At baseline, 20% (232 461) were current smokers, 28% (328 417) were ex-smokers, and 52% (619 774) were never-smokers. For 12-year mortality, those smoking at baseline had a mortality rate ratio of 2·76 (95% CI 2·71–2·81) compared with never-smokers, even though 44% (37 240/85 256) of the baseline smokers who responded to the 8-year resurvey had by then stopped smoking. Mortality was tripled, largely irrespective of age, in those still smoking at the 3-year resurvey (rate ratio 2·97, 2·88–3·07). Even for women smoking fewer than ten cigarettes per day at baseline, 12-year mortality was doubled (rate ratio 1·98, 1·91–2·04). Of the 30 most common causes of death, 23 were increased significantly in smokers; for lung cancer, the rate ratio was 21·4 (19·7–23·2). The excess mortality among smokers (in comparison with never-smokers) was mainly from diseases that, like lung cancer, can be caused by smoking. Among ex-smokers who had stopped permanently at ages 25–34 years or at ages 35–44 years, the respective relative risks were 1·05 (95% CI 1·00–1·11) and 1·20 (1·14–1·26) for all-cause mortality and 1·84 (1·45–2·34) and 3·34 (2·76–4·03) for lung cancer mortality. Thus, although some excess mortality remains among these long-term ex-smokers, it is only 3% and 10% of the excess mortality among continuing smokers. If combined with 2010 UK national death rates, tripled mortality rates among smokers indicate 53% of smokers and 22% of never-smokers dying before age 80 years, and an 11-year lifespan difference.
Interpretation
Among UK women, two-thirds of all deaths of smokers in their 50s, 60s, and 70s are caused by smoking; smokers lose at least 10 years of lifespan. Although the hazards of smoking until age 40 years and then stopping are substantial, the hazards of continuing are ten times greater. Stopping before age 40 years (and preferably well before age 40 years) avoids more than 90% of the excess mortality caused by continuing smoking; stopping before age 30 years avoids more than 97% of it.
Funding
Cancer Research UK, Medical Research Council.
doi:10.1016/S0140-6736(12)61720-6
PMCID: PMC3547248  PMID: 23107252
4.  Vascular disease in women: comparison of diagnoses in hospital episode statistics and general practice records in England 
Background
Electronic linkage to routine administrative datasets, such as the Hospital Episode Statistics (HES) in England, is increasingly used in medical research. Relatively little is known about the reliability of HES diagnostic information for epidemiological studies. In the United Kingdom (UK), general practitioners hold comprehensive records for individuals relating to their primary, secondary and tertiary care. For a random sample of participants in a large UK cohort, we compared vascular disease diagnoses in HES and general practice records to assess agreement between the two sources.
Methods
Million Women Study participants with a HES record of hospital admission with vascular disease (ischaemic heart disease [ICD-10 codes I20-I25], cerebrovascular disease [G45, I60-I69] or venous thromboembolism [I26, I80-I82]) between April 1st 1997 and March 31st 2005 were identified. In each broad diagnostic group and in women with no such HES diagnoses, a random sample of about a thousand women was selected for study. We asked each woman’s general practitioner to provide information on her history of vascular disease and this information was compared with the HES diagnosis record.
Results
Over 90% of study forms sent to general practitioners were returned and 88% of these contained analysable data. For the vast majority of study participants for whom information was available, diagnostic information from general practice and HES records was consistent. Overall, for 93% of women with a HES diagnosis of vascular disease, general practice records agreed with the HES diagnosis; and for 97% of women with no HES diagnosis of vascular disease, the general practitioner had no record of a diagnosis of vascular disease. For severe vascular disease, including myocardial infarction (I21-22), stroke, both overall (I60-64) and by subtype, and pulmonary embolism (I26), HES records appeared to be both reliable and complete.
Conclusion
Hospital admission data in England provide diagnostic information for vascular disease of sufficient reliability for epidemiological analyses.
doi:10.1186/1471-2288-12-161
PMCID: PMC3514155  PMID: 23110714
Hospital episode statistics; Hospital records; Medical records; Comparison; Diagnosis; Validation; Cohort study; Vascular disease; Myocardial infarction; Stroke; Pulmonary embolism; Venous thromboembolism; Ischaemic heart disease
5.  Different effects of age, adiposity and physical activity on the risk of ankle, wrist and hip fractures in postmenopausal women 
Bone  2012;50(6):1394-1400.
While increasing age, decreasing body mass index (BMI), and physical inactivity are known to increase hip fracture risk, whether these factors have similar effects on other common fractures is not well established. We used prospectively-collected data from a large cohort to examine the role of these factors on the risk of incident ankle, wrist and hip fractures in postmenopausal women. 1,155,304 postmenopausal participants in the Million Women Study with a mean age of 56.0 (SD 4.8) years, provided information about lifestyle, anthropometric, and reproductive factors at recruitment in 1996–2001. All participants were linked to National Health Service cause-specific hospital records for day-case or overnight admissions. During follow-up for an average of 8.3 years per woman, 6807 women had an incident ankle fracture, 9733 an incident wrist fracture, and 5267 an incident hip fracture. Adjusted absolute and relative risks (RRs) for incident ankle, wrist, and hip fractures were calculated using Cox regression models. Age-specific rates for wrist and hip fractures increased sharply with age, whereas rates for ankle fracture did not. Cumulative absolute risks from ages 50 to 84 years per 100 women were 2.5 (95%CI 2.2–2.8) for ankle fracture, 5.0 (95%CI 4.4–5.5) for wrist fracture, and 6.2 (95%CI 5.5–7.0) for hip fracture. Compared with lean women (BMI < 20 kg/m2), obese women (BMI ≥ 30 kg/m2) had a three-fold increased risk of ankle fracture (RR = 3.07; 95%CI 2.53–3.74), but a substantially reduced risk of wrist fracture and especially of hip fracture (RR = 0.57; 0.51–0.64 and 0.23; 0.21–0.27, respectively). Physical activity was associated with a reduced risk of hip fracture but was not associated with ankle or wrist fracture risk. Ankle, wrist and hip fractures are extremely common in postmenopausal women, but the associations with age, adiposity, and physical activity differ substantially between the three fracture sites.
Highlights
► Risk factors for ankle, wrist, and hip fractures differ by age, adiposity, and physical activity in postmenopausal women. ► Age-specific rates for wrist and hip fractures increased sharply with age, whereas rates for ankle fracture did not. ► Obese women had a three-fold increased risk of ankle fracture, when compared with lean women. ► Compared with lean women, obese women had a 43% and 77% reduced risk of wrist and hip fractures, respectively. ► Physical inactivity was associated with increased risk of hip fracture, but had little association with ankle or wrist fracture.
doi:10.1016/j.bone.2012.03.014
PMCID: PMC3405513  PMID: 22465850
Hip fracture; Wrist fracture; Ankle fracture; Physical activity; BMI; Postmenopausal women
6.  Incidence of and risk factors for Motor Neurone Disease in UK women: a prospective study 
BMC Neurology  2012;12:25.
Background
Motor neuron disease (MND) is a severe neurodegenerative disease with largely unknown etiology. Most epidemiological studies are hampered by small sample sizes and/or the retrospective collection of information on behavioural and lifestyle factors.
Methods
1.3 million women from the UK Million Women Study, aged 56 years on average at recruitment, were followed up for incident and/or fatal MND using NHS hospital admission and mortality data. Adjusted relative risks were calculated using Cox regression models.
Findings
During follow-up for an average of 9·2 years, 752 women had a new diagnosis of MND. Age-specific rates increased with age, from 1·9 (95% CI 1·3 – 2·7) to 12·5 (95% CI 10·2 – 15·3) per 100,000 women aged 50–54 to 70–74, respectively, giving a cumulative risk of diagnosis with the disease of 1·74 per 1000 women between the ages of 50 and 75 years. There was no significant variation in risk of MND with region of residence, socio-economic status, education, height, alcohol use, parity, use of oral contraceptives or hormone replacement therapy. Ever-smokers had about a 20% greater risk than never smokers (RR 1·19 95% CI 1·02 to 1·38, p = 0·03). There was a statistically significant reduction in risk of MND with increasing body mass index (pfor trend = 0·009): obese women (body mass index, 30 kg/m2 or more) had a 20% lower risk than women of normal body mass index (20 to <25 Kg/m2)(RR 0·78 95% CI 0·65-0·94; p = 0·03). This effect persisted after exclusion of the first three years of follow-up.
Interpretation
MND incidence in UK women rises rapidly with age, and an estimated 1 in 575 women are likely to be affected between the ages of 50 and 75 years. Smoking slightly increases the risk of MND, and adiposity in middle age is associated with a lower risk of the disease.
doi:10.1186/1471-2377-12-25
PMCID: PMC3512483  PMID: 22559076
Motor Neurone Disease; UK; Epidemiology; Incidence; Risk Factors; Smoking; Body Mass Index
7.  Injectable and Oral Contraceptive Use and Cancers of the Breast, Cervix, Ovary, and Endometrium in Black South African Women: Case–Control Study 
PLoS Medicine  2012;9(3):e1001182.
A case-control study conducted in South Africa provides new estimates of the risk of specific cancers of the female reproductive system associated with use of injectable and oral contraceptives.
Background
Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives.
Methods and Findings
We analysed data from a South African hospital-based case–control study of black females aged 18–79 y, comparing self-reported contraceptive use in patients with breast (n = 1,664), cervical (n = 2,182), ovarian (n = 182), and endometrial (n = 182) cancer, with self-reported contraceptive use in 1,492 control patients diagnosed with cancers with no known relationship to hormonal contraceptive use. We adjusted for potential confounding factors, including age, calendar year of diagnosis, education, smoking, alcohol, parity/age at first birth, and number of sexual partners. Among controls, 26% had used injectable and 20% had used oral contraceptives. For current and more recent users versus never users of oral or injectable contraceptives, the odds ratios (ORs) for breast cancer were significantly increased in users of oral and/or injectable contraceptives (OR 1.66, 95% CI 1.28–2.16, p<0.001) and separately among those exclusively using oral (1.57, 1.03–2.40, p = 0.04) and exclusively using injectable (OR 1.83, 1.31–2.55, p<0.001) contraceptives; corresponding ORs for cervical cancer were 1.38 (1.08–1.77, p = 0.01), 1.01 (0.66–1.56, p = 0.96), and 1.58 (1.16–2.15, p = 0.004). There was no significant increase in breast or cervical cancer risk among women ceasing hormonal contraceptive use ≥10 y previously (p = 0.3 and p = 0.9, respectively). For durations of use ≥5 y versus never use, the ORs of ovarian cancer were 0.60 (0.36–0.99, p = 0.04) for oral and/or injectable contraceptive use and 0.07 (0.01–0.49, p = 0.008) for injectable use exclusively; corresponding ORs for endometrial cancer were 0.44 (0.22–0.86, p = 0.02) and 0.36 (0.11–1.26, p = 0.1).
Conclusions
In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hormonal contraceptives are among the most commonly used medications. Globally, more than 210 million women currently use either hormonal contraceptive pills or injectable contraceptives. Contraceptive pills usually contain manmade versions of the female sex hormones estrogen and progesterone (the combined oral contraceptive, or “pill”); most injectable hormonal contraceptives contain only manmade progesterone preparations. Hormonal contraceptives, which prevent pregnancy by disrupting the cyclical changes in estrogen and progesterone levels that prepare the body for pregnancy, have revolutionized birth control since they first became available in the early 1960s. However, it is now known that taking the pill also influences women's risk of developing cancers of the female reproductive system. Current and recent users have an increased risk of developing breast and cervical cancer (the cervix is the structure that connects the womb to the vagina) compared to never users, although this increased risk quickly disappears when women stop taking the pill. By contrast, women who have used the pill have a reduced risk of developing ovarian cancer and cancer of the womb (endometrial cancer) compared to never users that increases with the duration of pill use and persists for many years after use ceases. These effects on reproductive system cancers are thought to occur because these cancers depend on naturally occurring sex hormones for their development and growth.
Why Was This Study Done?
Although the evidence that the pill influences the risk of developing cancers of the female reproductive system is extensive, much less is known about how injectable hormonal contraceptives affect cancer risk. In this hospital-based case–control study (a study that compares the characteristics of people with and without a specific condition), the researchers investigate the relationship between the use of oral and injectable hormonal contraceptives and cancers of the breast, cervix, ovary, and endometrium among black South African women. Injectable contraceptives have been used for longer in South Africa than elsewhere and are used more commonly than oral contraceptives among black South African women.
What Did the Researchers Do and Find?
As part of the Johannesburg Cancer Case Control Study, which recruits black patients attending Johannesburg public referral hospitals for cancer treatment, the researchers compared hormonal contraceptive use in women with breast, cervical, ovarian, or endometrial cancer with contraceptive use in women diagnosed with other cancers such as lung, colon, and rectal cancers, which are not known to be influenced by hormonal contraceptives. Among the controls, a quarter had used injectable contraceptives and a fifth had used oral contraceptives. After adjusting for other factors that might influence cancer risk such as age, smoking, and number of sexual partners, the odds ratio (OR) of breast cancer among current and recent users of oral and/or injectable contraceptives compared to never users was 1.66. That is, the risk of developing breast cancer among current and recent users of hormonal contraceptives was 1.66 times that among never users. For women using oral contraceptives exclusively or injectable contraceptives exclusively, the ORs of breast cancer were 1.57 and 1.83, respectively. There were also increases in cervical cancer risk among current and recent users of hormonal contraceptives compared to never users, but no significant increase in breast or cervical cancer risk among women who had ceased hormonal contraceptive use more than ten years previously. Finally, the use of hormonal contraceptives for more than five years reduced the risk of both ovarian and endometrial cancer.
What Do These Findings Mean?
These findings indicate that, among black women in South Africa, the use of oral or injectable hormonal contraceptives is associated with a transiently increased risk of breast and cervical cancer, and that extended use of these contraceptives is associated with a reduced risk of ovarian and endometrial cancer. Moreover, they suggest that the effects of oral versus injectable contraceptives on cancer risk do not differ substantially, although for endometrial and ovarian cancer the small number of cases exposed to injectable contraceptives limits the accuracy of the risk estimates. Other limitations of this study include the possibility that the findings may be affected by uncontrolled confounding. That is, women who used hormonal contraceptives may have shared other unidentified characteristics that affected their cancer risk. Nevertheless, these findings provide new information about the effects of oral and injectable hormonal contraceptives on cancer risk that should help women make informed decisions about their choice of contraceptive method.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001182.
The US National Cancer Institute provides information on breast cancer (including personal stories from breast cancer survivors), cervical cancer, ovarian cancer, and endometrial cancer for patients and health professionals, and a fact sheet on oral contraceptives and cancer risk (in English and Spanish)
Cancer Research UK also provides information on breast cancer, cervical cancer, ovarian cancer, and endometrial cancer and information about the birth control pill and cancer risk
Eyes on the Prize, an online support group for women who have had cancers of the female reproductive system, has personal stories; further personal stories about breast, cervical, and ovarian cancer are provided by the charity Healthtalkonline
doi:10.1371/journal.pmed.1001182
PMCID: PMC3295825  PMID: 22412354
8.  The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer 
Journal of Medical Screening  2011;18(4):210-212.
The number of women who would need to be screened regularly by mammography to prevent one death from breast cancer depends strongly on several factors, including the age at which regular screening starts, the period over which it continues, and the duration of follow-up after screening. Furthermore, more women would need to be INVITED for screening than would need to be SCREENED to prevent one death, since not all women invited attend for screening or are screened regularly. Failure to consider these important factors accounts for many of the major discrepancies between different published estimates. The randomised evidence indicates that, in high income countries, around one breast cancer death would be prevented in the long term for every 400 women aged 50–70 years regularly screened over a ten-year period.
doi:10.1258/jms.2011.011134
PMCID: PMC3266234  PMID: 22184734
9.  Height and cancer incidence in the Million Women Study: prospective cohort, and meta-analysis of prospective studies of height and total cancer risk 
The Lancet Oncology  2011;12(8):785-794.
Summary
Background
Epidemiological studies have shown that taller people are at increased risk of cancer, but it is unclear if height-associated risks vary by cancer site, or by other factors such as smoking and socioeconomic status. Our aim was to investigate these associations in a large UK prospective cohort with sufficient information on incident cancer to allow direct comparison of height-associated risk across cancer sites and in relation to major potential confounding and modifying factors.
Methods
Information on height and other factors relevant for cancer was obtained in 1996–2001 for middle-aged women without previous cancer who were followed up for cancer incidence. We used Cox regression models to calculate adjusted relative risks (RRs) per 10 cm increase in measured height for total incident cancer and for 17 specific cancer sites, taking attained age as the underlying time variable. We also did a meta-analysis of published results from prospective studies of total cancer risk in relation to height.
Findings
1 297 124 women included in our analysis were followed up for a total of 11·7 million person-years (median 9·4 years per woman, IQR 8·4–10·2), during which time 97 376 incident cancers occurred. The RR for total cancer was of 1·16 (95% CI 1·14–1·17; p<0·0001) for every 10 cm increase in height. Risk increased for 15 of the 17 cancer sites we assessed, and was statistically significant for ten sites: colon (RR per 10 cm increase in height 1·25, 95% CI 1·19–1·30), rectum (1·14, 1·07–1·22), malignant melanoma (1·32, 1·24–1·40), breast (1·17, 1·15–1·19), endometrium (1·19, 1·13–1·24), ovary (1·17, 1·11–1·23), kidney (1·29, 1·19–1·41), CNS (1·20, 1·12–1·29), non-Hodgkin lymphoma (1·21, 1·14–1·29), and leukaemia (1·26, 1·15–1·38). The increase in total cancer RR per 10 cm increase in height did not vary significantly by socioeconomic status or by ten other personal characteristics we assessed, but was significantly lower in current than in never smokers (p<0·0001). In current smokers, smoking-related cancers were not as strongly related to height as were other cancers (RR per 10 cm increase in height 1·05, 95% CI 1·01–1·09, and 1·17, 1·13–1·22, respectively; p=0·0004). In a meta-analysis of our study and ten other prospective studies, height-associated RRs for total cancer showed little variation across Europe, North America, Australasia, and Asia.
Interpretation
Cancer incidence increases with increasing adult height for most cancer sites. The relation between height and total cancer RR is similar in different populations.
Funding
Cancer Research UK and the UK Medical Research Council.
doi:10.1016/S1470-2045(11)70154-1
PMCID: PMC3148429  PMID: 21782509
10.  Reported frequency of physical activity in a large epidemiological study: relationship to specific activities and repeatability over time 
Background
How overall physical activity relates to specific activities and how reported activity changes over time may influence interpretation of observed associations between physical activity and health. We examine the relationships between various physical activities self-reported at different times in a large cohort study of middle-aged UK women.
Methods
At recruitment, Million Women Study participants completed a baseline questionnaire including questions on frequency of strenuous and of any physical activity. About 3 years later 589,896 women also completed a follow-up questionnaire reporting the hours they spent on a range of specific activities. Time spent on each activity was used to estimate the associated excess metabolic equivalent hours (MET-hours) and this value was compared across categories of physical activity reported at recruitment. Additionally, 18,655 women completed the baseline questionnaire twice, at intervals of up to 4 years; repeatability over time was assessed using the weighted kappa coefficient (κweighted) and absolute percentage agreement.
Results
The average number of hours per week women reported doing specific activities was 14.0 for housework, 4.5 for walking, 3.0 for gardening, 0.2 for cycling, and 1.4 for all strenuous activity. Time spent and the estimated excess MET-hours associated with each activity increased with increasing frequency of any or strenuous physical activity reported at baseline (tests for trend, P < 0.003), although the associations for housework were by far the weakest (Spearman correlations, 0.01 and -0.03 respectively for housework, and 0.11-0.37 for all other activities). Repeatability of responses to physical activity questions on the baseline questionnaire declined significantly over time. For strenuous activity, absolute agreement was 64% (κweighted = 0.71) for questionnaires administered less than 6 months apart, and 52% (κweighted = 0.51) for questionnaires more than 2 years apart. Corresponding values for any physical activity were 57% (κweighted = 0.67) and 47% (κweighted = 0.58).
Conclusions
In this cohort, responses to simple questions on the frequency of any physical activity and of strenuous activity asked at baseline were associated with hours spent on specific activities and the associated estimated excess MET-hours expended, reported 3 years later. The weakest associations were with housework. Agreement for identical questions asked on two occasions about the frequency of physical activity decreased over time.
doi:10.1186/1471-2288-11-97
PMCID: PMC3145605  PMID: 21831330
11.  Breast Cancer Risk in Relation to the Interval Between Menopause and Starting Hormone Therapy 
Background
Although breast cancer risk is greater in users of estrogen–progestin than estrogen-only formulations of menopausal hormonal therapy, reports on their effects have been somewhat inconsistent. We investigated whether the timing of these therapies affected breast cancer incidence.
Methods
A total of 1 129 025 postmenopausal UK women provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk. We used Cox regression to estimate adjusted relative risks (RRs) of breast cancer in hormonal therapy users vs never users and calculated standardized incidence rates. All statistical tests were two-sided.
Results
During 4.05 million woman-years of follow-up, 15 759 incident breast cancers occurred, with 7107 in current users of hormonal therapy. Breast cancer incidence was increased in current users of hormonal therapy, returning to that of never users a few years after use had ceased. The relative risks for breast cancer in current users were greater if hormonal therapy was begun before or soon after menopause than after a longer gap (Pheterogeneity < .001, for both estrogen-only and estrogen-progestin formulations). Among current users of estrogen-only formulations, there was little or no increase in risk if use began 5 years or more after menopause (RR = 1.05, 95% confidence interval [CI] = 0.89 to 1.24), but risk was statistically significantly increased if use began before or less than 5 years after menopause (RR = 1.43, 95% CI = 1.35 to 1.51). A similar pattern was observed among current users of estrogen–progestin formulations (RR = 1.53, 95% CI = 1.38 to 1.70, and RR = 2.04, 95% CI = 1.95 to 2.14, respectively). At 50–59 years of age, annual standardized incidence rates for breast cancer were 0.30% (95% CI = 0.29% to 0.31%) among never users of hormone therapy and 0.43% (95% CI = 0.42% to 0.45%) and 0.61% (95% CI = 0.59% to 0.64%), respectively, among current users of estrogen-only and estrogen–progestin formulations who began use less than 5 years after menopause.
Conclusions
There was substantial heterogeneity in breast cancer risk among current users of hormonal therapy. Risks were greater among users of estrogen–progestin than estrogen-only formulations and if hormonal therapy started at around the time of menopause than later.
doi:10.1093/jnci/djq527
PMCID: PMC3039726  PMID: 21278356
12.  Lifetime body size and reproductive factors: comparisons of data recorded prospectively with self reports in middle age 
Background
Data on lifetime exposures are often self-reported in epidemiologic studies, sometimes many years after the relevant age. Validity of self-reported data is usually inferred from their agreement with measured values, but few studies directly quantify the likely effects of reporting errors in body size and reproductive history variables on estimates of disease-exposure associations.
Methods
The MRC National Survey of Health and Development (NSHD) and the Million Women Study (MWS) are UK population-based prospective cohorts. The NSHD recruited participants at birth in 1946 and has followed them at regular intervals since then, whereas the MWS recruited women in middle age. For 541 women who were participants in both studies, we used statistical measures of association and agreement to compare self-reported MWS data on body size throughout life and reproductive history, obtained in middle age, to NSHD data measured or reported close to the relevant ages. Likely attenuation of estimates of linear disease-exposure associations due to the combined effects of random and systematic errors was quantified using regression dilution ratios (RDRs).
Results
Data from the two studies were very strongly correlated for current height, weight and body mass index, and age at menopause (Pearson r = 0.91-0.95), strongly correlated for birth weight, parental heights, current waist and hip circumferences and waist-to-height ratio (r = 0.67-0.80), and moderately correlated for age at menarche and waist-to-hip ratio (r = 0.52-0.57). Self-reported categorical body size and clothes size data for various ages were moderately to strongly associated with anthropometry collected at the relevant times (Spearman correlations 0.51-0.79). Overall agreement between the studies was also good for most quantitative variables, although all exhibited both random and systematic reporting error. RDRs ranged from 0.66 to 0.86 for most variables (slight to moderate attenuation), except weight and body mass index (1.02 and 1.04, respectively; little or no attenuation), and age at menarche, birth weight and waist-to-hip ratio (0.44, 0.59 and 0.50, respectively; substantial attenuation).
Conclusions
This study provides some evidence that self-reported data on certain anthropometric and reproductive factors may be adequate for describing disease-exposure associations in large epidemiological studies, provided that the effects of reporting errors are quantified and the results are interpreted with caution.
doi:10.1186/1471-2288-11-7
PMCID: PMC3034712  PMID: 21241500
13.  Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort 
Objective To examine the hypothesis that risk of oesophageal, but not of gastric or colorectal, cancer is increased in users of oral bisphosphonates.
Design Nested case-control analysis within a primary care cohort of about 6 million people in the UK, with prospectively recorded information on prescribing of bisphosphonates.
Setting UK General Practice Research Database cohort.
Participants Men and women aged 40 years or over—2954 with oesophageal cancer, 2018 with gastric cancer, and 10 641 with colorectal cancer, diagnosed in 1995-2005; five controls per case matched for age, sex, general practice, and observation time.
Main outcome measures Relative risks for incident invasive cancers of the oesophagus, stomach, and colorectum, adjusted for smoking, alcohol, and body mass index.
Results The incidence of oesophageal cancer was increased in people with one or more previous prescriptions for oral bisphosphonates compared with those with no such prescriptions (relative risk 1.30, 95% confidence interval 1.02 to1.66; P=0.02). Risk of oesophageal cancer was significantly higher for 10 or more prescriptions (1.93, 1.37 to 2.70) than for one to nine prescriptions (0.93, 0.66 to 1.31) (P for heterogeneity=0.002), and for use for over 3 years (on average, about 5 years: relative risk v no prescription, 2.24, 1.47 to 3.43). Risk of oesophageal cancer did not differ significantly by bisphosphonate type, and risk in those with 10 or more bisphosphonate prescriptions did not vary by age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, or corticosteroids. Cancers of the stomach and colorectum were not associated with prescription of bisphosphonate: relative risks for one or more versus no prescriptions were 0.87 (0.64 to 1.19) and 0.87 (0.77 to 1.00). The specificity of the association for oesophageal cancer argues against methodological problems in the selection of cases and controls or in the analysis.
Conclusions The risk of oesophageal cancer increased with 10 or more prescriptions for oral bisphosphonates and with prescriptions over about a five year period. In Europe and North America, the incidence of oesophageal cancer at age 60-79 is typically 1 per 1000 population over five years, and this is estimated to increase to about 2 per 1000 with five years’ use of oral bisphosphonates.
doi:10.1136/bmj.c4444
PMCID: PMC2933354  PMID: 20813820
14.  Body mass index and risk of liver cirrhosis in middle aged UK women: prospective study 
Objective To determine the relation between body mass index (BMI) and liver cirrhosis and the contribution that BMI and alcohol consumption make to the incidence of liver cirrhosis in middle aged women in the UK.
Design Prospective cohort study (Million Women Study).
Setting Women recruited from 1996 to 2001 in NHS breast screening centres and followed by record linkage to routinely collected information on hospital admissions and deaths.
Participants 1 230 662 women (mean age 56 years at recruitment) followed for an average of 6.2 years.
Main outcome measures Relative risk and absolute risk of first hospital admission with or death from liver cirrhosis adjusted for age, recruitment region, alcohol consumption, smoking, socioeconomic status, and physical activity.
Results 1811 women had a first hospital admission with or died from liver cirrhosis during follow-up. Among women with a BMI of 22.5 or above, increasing BMI was associated with an increased incidence of liver cirrhosis: the adjusted relative risk of cirrhosis increased by 28% (relative risk 1.28, 95% confidence interval 1.19 to 1.38; P<0.001) for every 5 unit increase in BMI. Although the relative increase in the risk of liver cirrhosis per 5 unit increase in BMI did not differ significantly according to the amount of alcohol consumed, the absolute risk did. Among women who reported drinking less than 70 g alcohol per week, the absolute risk of liver cirrhosis per 1000 women over five years was 0.8 (0.7 to 0.9) for those with a BMI between 22.5 and 25 and 1.0 (0.9 to 1.2) for those with a BMI of 30 or more. Among women who reported drinking 150 g alcohol or more per week, the corresponding figures were 2.7 (2.1 to 3.4) and 5.0 (3.8 to 6.6).
Conclusions Excess body weight increases the incidence of liver cirrhosis. In middle aged women in the UK, an estimated 17% of incident or fatal liver cirrhosis is attributable to excess body weight. This compares with an estimated 42% attributable to alcohol.
doi:10.1136/bmj.c912
PMCID: PMC2837146  PMID: 20223875
15.  Gene–environment interactions in 7610 women with breast cancer: prospective evidence from the Million Women Study 
Lancet  2010;375(9732):2143-2151.
Summary
Background
Information is scarce about the combined effects on breast cancer incidence of low-penetrance genetic susceptibility polymorphisms and environmental factors (reproductive, behavioural, and anthropometric risk factors for breast cancer). To test for evidence of gene–environment interactions, we compared genotypic relative risks for breast cancer across the other risk factors in a large UK prospective study.
Methods
We tested gene–environment interactions in 7610 women who developed breast cancer and 10 196 controls without the disease, studying the effects of 12 polymorphisms (FGFR2-rs2981582, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, 2p-rs4666451, 5p12-rs981782, CASP8-rs1045485, LSP1-rs3817198, 5q-rs30099, TGFB1-rs1982073, and ATM-rs1800054) in relation to prospectively collected information about ten established environmental risk factors (age at menarche, parity, age at first birth, breastfeeding, menopausal status, age at menopause, use of hormone replacement therapy, body-mass index, height, and alcohol consumption).
Findings
After allowance for multiple testing none of the 120 comparisons yielded significant evidence of a gene–environment interaction. By contrast with previous suggestions, there was little evidence that the genotypic relative risks were affected by use of hormone replacement therapy, either overall or for oestrogen-receptor-positive disease. Only one of the 12 polymorphisms was correlated with any of the ten other risk factors: carriers of the high-risk C allele of MAP3K1-rs889312 were significantly shorter than non-carriers (mean height 162·4 cm [95% CI 162·1–162·7] vs 163·1 cm [162·9–163·2]; p=0·01 after allowance for multiple testing).
Interpretation
Risks of breast cancer associated with low-penetrance susceptibility polymorphisms do not vary significantly with these ten established environmental risk factors.
Funding
Cancer Research UK and the UK Medical Research Council.
doi:10.1016/S0140-6736(10)60636-8
PMCID: PMC2890858  PMID: 20605201
16.  Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study 
Objective To examine the duration and magnitude of increased risk of venous thromboembolism after different types of surgery.
Design Prospective cohort study (Million Women Study).
Setting Questionnaire data from the Million Women Study linked with hospital admission and death records.
Participants 947 454 middle aged women in the United Kingdom recruited in 1996-2001 and followed by record linkage to routinely collected NHS data on hospital admissions and deaths. During follow-up 239 614 admissions were for surgery; 5419 women were admitted, and a further 270 died, from venous thromboembolism.
Main outcome measures Adjusted relative risks and standardised incidence rates for hospital admission or death from venous thromboembolism (pulmonary embolism or deep vein thrombosis), by time since and type of surgery.
Results Compared with not having surgery, women were 70 times more likely to be admitted with venous thromboembolism in the first six weeks after an inpatient operation (relative risk 69.1, 95% confidence interval 63.1 to 75.6) and 10 times more likely after a day case operation (9.6, 8.0 to 11.5). The risks were lower but still substantially increased 7-12 weeks after surgery (19.6, 16.6 to 23.1 and 5.5, 4.3 to 7.0, respectively). This pattern of risk was similar for pulmonary embolism (n=2487) and deep venous thrombosis (n=3529). The postoperative risks of venous thromboembolism varied considerably by surgery type, with highest relative risks after inpatient surgery for hip or knee replacement and for cancer—1-6 weeks after surgery the relative risks were, respectively, 220.6 (187.8 to 259.2) and 91.6 (73.9 to 113.4).
Conclusion The risk of deep vein thrombosis and pulmonary embolism after surgery is substantially increased in the first 12 postoperative weeks, and varies considerably by type of surgery. An estimated 1 in 140 middle aged women undergoing inpatient surgery in the UK will be admitted with venous thromboembolism during the 12 weeks after surgery (1 in 45 after hip or knee replacement and 1 in 85 after surgery for cancer), compared with 1 in 815 after day case surgery and only 1 in 6200 women during a 12 week period without surgery.
doi:10.1136/bmj.b4583
PMCID: PMC2788913  PMID: 19959589
17.  Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis 
PLoS Medicine  2009;6(11):e1000181.
Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause.
Background
Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture.
Methods and Findings
Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.
Conclusions
At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anyone can break a hip but most hip fractures occur in elderly people. As people age, their bones gradually lose minerals and become less dense, which weakens the bones and makes them more susceptible to fracture. Because women lose bone density faster than men as they age and because women constitute the majority of the elderly, three-quarters of hip fractures occur in women. Hip fractures can cause long-term health problems and premature death. Thus, although surgical repair of a broken hip usually only requires a hospital stay of about a week, a quarter of elderly people who were living independently before their fracture have to stay in a nursing home for at least a year after their injury and a fifth of elderly people who break a hip die within the year. Most hip fractures are caused by falls. Regular exercise to improve strength and balance combined with review of medicines (to reduce side effects and interactions), regular eye examinations, and the removal of fall hazards from the home can help to prevent hip fractures in elderly people.
Why Was This Study Done?
Bone density decreases very rapidly in women immediately after menopause—the time when menstruation permanently stops—and then continues to decrease more slowly with age. Most women have their menopause in their early 50s but menopause can occur in younger women. Early menopause is thought to be a risk factor for osteoporosis (thinning of the bones) and fractures later in life but little is known about how menopause influences hip fracture risk as women age. In this prospective study (a type of study in which a group of people is followed for several years to see whether they develop a particular condition), the researchers investigate the incidence of hip fractures in relation to age, menopausal status, and age at menopause among the participants of the Million Women Study. This study, which recruited 1.3 million women aged 50–64 years who attended UK breast cancer screening clinics between 1996 and 2001, has been investigating how reproductive and lifestyle factors affect women's health.
What Did the Researchers Do and Find?
At enrollment and three years later, the study participants provided information about their menopausal status and other health and lifestyle factors likely to affect their fracture risk. From these data, the researchers identified more than half a million women who had never used hormone replacement therapy (which reduces fracture risk) and who had given complete information about their menopausal status. They then looked for statistical associations between the occurrence of a first hip fracture in these women over the next few years and their age, menopausal status, and age at menopause. Among women aged 50–54 years, postmenopausal women were twice as likely to have a hip fracture as premenopausal women. Among postmenopausal women, the incidence of hip fractures increased steeply with age and was seven times higher in 70–74-year olds than in 50–54-year olds. Women who had their menopause before age 45 had a slightly increased risk of hip fracture but any effect of age at menopause on the risk of hip fracture was small compared to the effect of age itself, and the slightly increased risk may have been due to other factors that could not be fully accounted for in the analysis.
What Do These Findings Mean?
These findings indicate that around the time of menopause, although hip fractures are rare, the risk of a fracture in postmenopausal women is twice that in premenopausal women. The findings also show that among postmenopausal women, age is the major determinant of hip fracture risk and that for women of a given age, their age at menopause has little effect on hip fracture risk. Women attending breast cancer screening clinics and completing questionnaires about their health may not be representative of the general population. Furthermore, these findings rely on women self-reporting their menopausal status accurately. Nevertheless, the results of this study suggest that clinicians advising women about hip fracture prevention should probably base their advice on the woman's age and on age-related factors such as frailty rather than on factors related to menopause. Clinicians can also now reassure elderly women who had an early menopause that their risk of hip fracture is unlikely to be higher than that of similar women who had a later menopause.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000181.
The American Academy of Orthopaedic Surgeons has detailed information about hip fractures
The US National Institute of Arthritis and Muscoloskeletal and Skin Diseases has an interactive feature called “Check up on your bones and provides detailed information about osteoporosis, including advice on fall prevention
The US Centers for Disease Control and Prevention has a fact sheet about hip fractures among older adults
MedlinePlus has links to resources about hip fracture, osteoporosis, and menopause (in English and Spanish)
More information on the Million Women Study is available
doi:10.1371/journal.pmed.1000181
PMCID: PMC2766835  PMID: 19901981
18.  Reproductive history and pancreatic cancer incidence and mortality in a cohort of post-menopausal women 
There is inconsistent evidence about the effect of reproductive history on women’s risk of pancreatic cancer. In the Million Women Study, a prospective cohort of middle-aged women in the UK, we examined associations between reproductive history and pancreatic cancer incidence and mortality, controlling for age, socioeconomic status, geographic region, body mass index, smoking and history of diabetes. During 7.1 million person-years of follow-up in 995,192 post-menopausal women there were 1,182 incident pancreatic cancers. Pancreatic cancer incidence and mortality did not vary significantly with age at menarche, number of children, age at first birth, breastfeeding, type of menopause, age at menopause or time since menopause. Any effect of reproductive history and pancreatic cancer risk in women is likely to be weak, if it exists at all.
doi:10.1158/1055-9965.EPI-08-1134
PMCID: PMC2722795  PMID: 19423523
pancreatic cancer; reproductive history; parity; menopause; menarche
19.  Inequalities in reported use of breast and cervical screening in Great Britain: analysis of cross sectional survey data 
Objective To investigate the relation between women’s reported use of breast and cervical screening and sociodemographic characteristics.
Design Cross sectional multipurpose survey.
Setting Private households, Great Britain.
Population 3185 women aged 40-74 interviewed in the National Statistics Omnibus Survey 2005-7.
Main outcome measures Ever had a mammogram, ever had a cervical smear, and, for each, timing of most recent screen.
Results 91% (95% confidence interval 90% to 92%) of women aged 40-74 years reported ever having had a cervical smear, and 93% (92% to 94%) of those aged 53-74 years reported ever having had a mammogram; 3% (2% to 4%) of women aged 53-74 years had never had either breast or cervical screening. Women were significantly more likely to have had a mammogram if they lived in households with cars (compared with no car: one car, odds ratio 1.67, 95% confidence interval 1.06 to 2.62; two or more cars, odds ratio 2.65, 1.34 to 5.26), and in owner occupied housing (compared with rented housing: own with mortgage, odds ratio 2.12, 1.12 to 4.00; own outright, odds ratio 2.19, 1.39 to 3.43), but no significant differences by ethnicity, education, occupation, or region were found. For cervical screening, ethnicity was the most important predictor; white British women were significantly more likely to have had a cervical smear than were women of other ethnicity (odds ratio 2.20, 1.41 to 3.42). Uptake of cervical screening was greater among more educated women but was not significantly associated with cars, housing tenure, or region.
Conclusions Most (84%) eligible women report having had both breast and cervical screening, but 3% report never having had either. Some inequalities exist in the reported use of screening, which differ by screening type; indicators of wealth were important for breast screening and ethnicity for cervical screening. The routine collection within general practice of additional sociodemographic information would aid monitoring of inequalities in screening coverage and inform policies to correct them.
doi:10.1136/bmj.b2025
PMCID: PMC2697310  PMID: 19531549
20.  Gallbladder disease and use of transdermal versus oral hormone replacement therapy in postmenopausal women: prospective cohort study 
Objective To determine whether transdermal compared with oral use of hormone replacement therapy reduces the risk of gallbladder disease in postmenopausal women.
Design Prospective cohort study (Million Women Study).
Setting Women registered with the National Health Service (NHS) in England and Scotland.
Participants 1 001 391 postmenopausal women (mean age 56) recruited between 1996 and 2001 from NHS breast screening centres and followed by record linkage to routinely collected NHS hospital admission data for gallbladder disease.
Main outcome measures Adjusted relative risk and standardised incidence rates of hospital admission for gallbladder disease or cholecystectomy according to use of hormone replacement therapy.
Results During follow-up 19 889 women were admitted for gallbladder disease; 17 190 (86%) had a cholecystectomy. Compared with never users of hormone replacement therapy, current users were more likely to be admitted for gallbladder disease (relative risk 1.64, 95% confidence interval 1.58 to 1.69) but risks were substantially lower with transdermal therapy than with oral therapy (relative risk 1.17, 1.10 to 1.24 v 1.74, 1.68 to 1.80; heterogeneity P<0.001). Among women using oral therapy, equine oestrogens were associated with a slightly greater risk of gallbladder disease than estradiol (relative risk 1.79, 1.72 to 1.87 v 1.62, 1.54 to 1.70; heterogeneity P<0.001) and higher doses of oestrogen increased the risk more than lower doses: for equine oestrogens >0.625 mg, 1.91 (1.78 to 2.04) v ≤0.625 mg, 1.76 (1.68 to 1.84); heterogeneity P=0.02; estradiol >1 mg, 1.68 (1.59 to 1.77) v ≤1 mg, 1.44 (1.31 to 1.59); heterogeneity P=0.003. The risk of gallbladder disease decreased with time since stopping therapy (trend P=0.004). Results were similar taking cholecystectomy as the outcome. Standardised hospital admission rates per 100 women over five years for cholecystectomy were 1.1 in never users, 1.3 with transdermal therapy, and 2.0 with oral therapy.
Conclusion Gallbladder disease is common in postmenopausal women and use of hormone replacement therapy increases the risk. Use of transdermal therapy rather than oral therapy over a five year period could avoid one cholecystectomy in every 140 users.
doi:10.1136/bmj.a386
PMCID: PMC2500203  PMID: 18617493
21.  Do women know that the risk of breast cancer increases with age? 
It is important that women know that the risk of breast cancer increases with age. Women's knowledge of the increased risk will help to inform their health-seeking behaviour. This study shows that over 50% of women wrongly believe that the risk does not vary with age. Only 1% are correctly informed, believing that the oldest group of women are at the greatest risk of breast cancer. Those working in primary care need to be aware of this lack of knowledge when patients consult.
PMCID: PMC2047017  PMID: 17504593
age; breast cancer; knowledge
22.  Cancer incidence and mortality in relation to body mass index in the Million Women Study: cohort study 
BMJ : British Medical Journal  2007;335(7630):1134.
Objective To examine the relation between body mass index (kg/m2) and cancer incidence and mortality.
Design Prospective cohort study.
Participants 1.2 million UK women recruited into the Million Women Study, aged 50-64 during 1996-2001, and followed up, on average, for 5.4 years for cancer incidence and 7.0 years for cancer mortality.
Main outcome measures Relative risks of incidence and mortality for all cancers, and for 17 specific types of cancer, according to body mass index, adjusted for age, geographical region, socioeconomic status, age at first birth, parity, smoking status, alcohol intake, physical activity, years since menopause, and use of hormone replacement therapy.
Results 45 037 incident cancers and 17 203 deaths from cancer occurred over the follow-up period. Increasing body mass index was associated with an increased incidence of endometrial cancer (trend in relative risk per 10 units=2.89, 95% confidence interval 2.62 to 3.18), adenocarcinoma of the oesophagus (2.38, 1.59 to 3.56), kidney cancer (1.53, 1.27 to 1.84), leukaemia (1.50, 1.23 to 1.83), multiple myeloma (1.31, 1.04 to 1.65), pancreatic cancer (1.24, 1.03 to 1.48), non-Hodgkin's lymphoma (1.17, 1.03 to 1.34), ovarian cancer (1.14, 1.03 to 1.27), all cancers combined (1.12, 1.09 to 1.14), breast cancer in postmenopausal women (1.40, 1.31 to 1.49) and colorectal cancer in premenopausal women (1.61, 1.05 to 2.48). In general, the relation between body mass index and mortality was similar to that for incidence. For colorectal cancer, malignant melanoma, breast cancer, and endometrial cancer, the effect of body mass index on risk differed significantly according to menopausal status.
Conclusions Increasing body mass index is associated with a significant increase in the risk of cancer for 10 out of 17 specific types examined. Among postmenopausal women in the UK, 5% of all cancers (about 6000 annually) are attributable to being overweight or obese. For endometrial cancer and adenocarcinoma of the oesophagus, body mass index represents a major modifiable risk factor; about half of all cases in postmenopausal women are attributable to overweight or obesity.
doi:10.1136/bmj.39367.495995.AE
PMCID: PMC2099519  PMID: 17986716
23.  The relationship between anti-HPV-16 IgG seropositivity and cancer of the cervix, anogenital organs, oral cavity and pharynx, oesophagus and prostate in a black South African population 
Background
Human papillomavirus type 16 (HPV-16) infection is an important cause of cervical cancer, other anogenital cancers and, possibly, some oral and pharyngeal cancers. The association of HPV-16 with oesophageal and with prostate cancers has not been firmly established.
Methods
We analysed sera from 3,757 HIV seronegative black South Africans using an anti-HPV IgG enzyme-linked immunosorbent assay (ELISA). The subjects were recruited from 1995 to 2000 as part of an ongoing cancer case control study. Cases were patients with newly diagnosed cancers of the cervix (n = 946), other anogenital organs (n = 80), the oral cavity and pharynx (n = 102), the oesophagus (n = 369) or the prostate (n = 205). The comparison group consisted of 2,055 age and sex-matched patients randomly selected from the same data base, diagnosed at the same hospitals, but with a vascular disease or with a cancer unrelated to HPV infection. Subjects' sera were randomly and blindly allocated onto ELISA plates. Optical density (OD) levels of anti-HPV-16 IgG of > 0.45 and ≥ 0.767 were taken to be cut-offs for negative, medium and high antibody levels.
Results
After adjustment for potential confounders, cancer types that showed a statistically significant association with increased anti-HPV-16 IgG antibody (Ab) levels were cancer of the cervix (OR for medium Ab levels = 1.6, and for high = 2.4, p < 0.0001), cancers of other anogenital organs (OR for medium or high Ab levels = 2.5, p = 0.002), and cancer of the oesophagus (OR for medium Ab = 1.3, and high Ab levels = 1.6 p = 0.002). Cancers of the oral cavity and pharynx showed a borderline significant association in the unadjusted model (p = 0.05) but after adjustment for confounding the trend in relation to Ab levels was positive but not statistically significant (OR for medium Ab = 1.1, and high Ab = 1.5 p = 0.13). Prostate cancer was not associated with HPV-16 seropositivity (OR for medium Ab level = 1.4, and for high Ab level = 1.3, p = 0.3).
Conclusion
If there is indeed an association between HPV-16 and oesophageal and possibly also some oral cavity and pharyngeal cancers, then emerging HPV vaccines may also reduce, at least in part, the incidence of these leading cancer types.
doi:10.1186/1750-9378-2-6
PMCID: PMC1821007  PMID: 17331260
24.  Helicobacter pylori and cancer among adults in Uganda 
Data from Africa on infection with Helicobacter pylori (H. pylori) are sparse. Therefore, as part of an epidemiological study of cancer in Uganda, we investigated the prevalence and determinants of antibodies against H. pylori among 854 people with different cancer types and benign tumours. Patients were recruited from hospitals in Kampala, Uganda, interviewed about various demographic and lifestyle factors and tested for antibodies against H. pylori. In all patients combined, excluding those with stomach cancer (which has been associated with H. pylori infection), the prevalence of antibodies was 87% (723/833) overall, but declined with increasing age (p = 0.02) and was lower among people who were HIV seropositive compared to seronegative (p < 0.001). Otherwise, there were few consistent epidemiological associations. Among those with stomach cancer, 18/21 (86%) had anti-H. pylori antibodies (odds ratio 0.8, 95% confidence intervals 0.2–2.9, p = 0.7; estimated using all other patients as controls, with adjustment for age, sex and HIV serostatus). No other cancer site or type was significantly associated with anti-H. pylori antibodies. The prevalence of H. pylori reported here is broadly in accord with results from other developing countries, although the determinants of infection and its' role in the aetiology of gastric cancer in Uganda remain unclear.
doi:10.1186/1750-9378-1-5
PMCID: PMC1660530  PMID: 17150134
25.  Hormone replacement therapy and false positive recall in the Million Women Study: patterns of use, hormonal constituents and consistency of effect 
Breast Cancer Research  2005;8(1):R8.
Introduction
Current and recent users of hormone replacement therapy (HRT) have an increased risk of being recalled to assessment at mammography without breast cancer being diagnosed ('false positive recall'), but there is limited information on the effects of different patterns of HRT use on this. The aim of this study is to investigate in detail the relationship between patterns of use of HRT and false positive recall.
Methods
A total of 87,967 postmenopausal women aged 50 to 64 years attending routine breast cancer screening at 10 UK National Health Service Breast Screening Units from 1996 to 1998 joined the Million Women Study by completing a questionnaire before screening and were followed for their screening outcome.
Results
Overall, 399 (0.5%) participants were diagnosed with breast cancer and 2,629 (3.0%) had false positive recall. Compared to never users of HRT, the adjusted relative risk (95% CI) of false positive recall was: 1.62 (1.43–1.83), 1.80 (1.62–2.01) and 0.76 (0.52–1.10) in current users of oestrogen-only HRT, oestrogen-progestagen HRT and tibolone, respectively (p (heterogeneity) < 0.0001); 1.65 (1.43–1.91), 1.49 (1.22–1.81) and 2.11 (1.45–3.07) for current HRT used orally, transdermally or via an implant, respectively (p (heterogeneity) = 0.2); and 1.84 (1.67–2.04) and 1.75 (1.49–2.06) for sequential and continuous oestrogen-progestagen HRT, respectively (p (heterogeneity) = 0.6). The relative risk of false positive recall among current users appeared to increase with increasing time since menopause, but did not vary significantly according to any other factors examined, including duration of use, hormonal constituents, dose, whether single- or two-view screening was used, or the woman's personal characteristics.
Conclusion
Current use of oestrogen-only and oestrogen-progestagen HRT, but not tibolone, increases the risk of false positive recall at screening.
doi:10.1186/bcr1364
PMCID: PMC1413983  PMID: 16417651

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