Siân Sweetland

Risk factors for adenocarcinoma and squamous cell carcinoma of the cervix in women aged 20–44 years: the UK National Case–Control Study of Cervical Cancer

We report results on risk factors for invasive squamous cell and adenocarcinomas of the cervix in women aged 20–44 years from the UK National Case–Control Study of Cervical Cancer, including 180 women with adenocarcinoma, 391 women with squamous cell carcinoma and 923 population controls. The risk of both squamous cell and adenocarcinoma was strongly related to the lifetime number of sexual partners, and, independently, to age at first intercourse. The risk of both types of cervical cancer increased with increasing duration of use of oral contraceptives, and this effect was most marked in current and recent users of oral contraceptives. The risk of squamous cell carcinoma was associated with high parity and the risk of both squamous cell and adenocarcinoma increased with early age at first birth. Long duration smoking (20 or more years) was associated with a two-fold increase in the risk of squamous cell carcinoma, but smoking was not associated with the risk of adenocarcinoma. Further studies are needed to confirm the suggestion from this and other studies of differences in risk related to smoking between squamous cell and adenocarcinomas of the cervix.

Comparison of risk factors for squamous cell and adenocarcinomas of the cervix: a meta-analysis

While most cancers of the uterine cervix are squamous cell carcinomas, the relative and absolute incidence of adenocarcinoma of the uterine cervix has risen in recent years. It is not clear to what extent risk factors identified for squamous cell carcinoma of the cervix are shared by cervical adenocarcinomas. We used data from six case–control studies to compare directly risk factors for cervical adenocarcinoma (910 cases) and squamous cell carcinoma (5649 cases) in a published data meta-analysis. The summary odds ratios and tests for differences between these summaries for the two histological types were estimated using empirically weighted least squares. A higher lifetime number of sexual partners, earlier age at first intercourse, higher parity and long duration of oral contraceptive use were risk factors for both histological types. Current smoking was associated with a significantly increased risk of squamous cell carcinoma, with a summary odds ratio of 1.47 (95% confidence interval: 1.15–1.88), but not of adenocarcinoma (summary odds ratio=0.82 (0.60–1.11); test for heterogeneity between squamous cell and adenocarcinoma for current smoking: P=0.001). The results of this meta-analysis of published data suggest that squamous cell and adenocarcinomas of the uterine cervix, while sharing many risk factors, may differ in relation to smoking. Further evidence is needed to confirm this in view of the limited data available.

Body Mass Index, Surgery, and Risk of Venous Thromboembolism in Middle-Aged Women A Cohort Study

Background— Obesity and surgery are known risk factors for venous thromboembolism (VTE), but there is limited information about the independent effects of obesity on the incidence of postoperative VTE. We linked questionnaire data from the Million Women Study with hospital admission and death records to examine the risk of VTE in relation to body mass index (BMI) both in the absence of surgery and in the first 12 weeks following an operation. Methods and Results— Overall, 1 170 495 women (mean age, 56.1 years) recruited in 1996 to 2001 through the National Health Service Breast Screening Programme in England and Scotland were followed for an average of 6 years, during which time 6438 were admitted to hospital or died of VTE. The adjusted relative risks of VTE increased progressively with increasing BMI and women with a BMI ≥35 kg/m2 were 3–4 times as likely to develop VTE as those with a BMI 22.5 to 24.9 (relative risk 3.45 [95% CI 3.09–3.86]). Overweight and obese women were more likely than lean women to be admitted for surgery and also to develop postoperative VTE. During a 12-week period without surgery, the incidence rates of VTE per 1000 women with a BMI <25 and ≥25 were 0.10 (0.09–0.10) and 0.19 (0.18–0.20); the corresponding rates in the 12 weeks following day and inpatient surgery were, respectively, about 4 and 40 times higher. Conclusions— VTE risk increases with increasing BMI and the associated excess risk is much greater after surgery than without surgery.

Endometrial cancer and oral contraceptives: an individual participant meta-analysis of 27 276 women with endometrial cancer from 36 epidemiological studies

BACKGROUND Oral contraceptives are known to reduce the incidence rate of endometrial cancer, but it is uncertain how long this effect lasts after use ceases, or whether it is modified by other factors. METHODS Individual participant datasets were sought from principal investigators and provided centrally for 27 276 women with endometrial cancer (cases) and 115 743 without endometrial cancer (controls) from 36 epidemiological studies. The relative risks (RRs) of endometrial cancer associated with oral contraceptive use were estimated using logistic regression, stratified by study, age, parity, body-mass index, smoking, and use of menopausal hormone therapy. FINDINGS The median age of cases was 63 years (IQR 57-68) and the median year of cancer diagnosis was 2001 (IQR 1994-2005). 9459 (35%) of 27 276 cases and 45 625 (39%) of 115 743 controls had ever used oral contraceptives, for median durations of 3·0 years (IQR 1-7) and 4·4 years (IQR 2-9), respectively. The longer that women had used oral contraceptives, the greater the reduction in risk of endometrial cancer; every 5 years of use was associated with a risk ratio of 0·76 (95% CI 0·73-0·78; p<0·0001). This reduction in risk persisted for more than 30 years after oral contraceptive use had ceased, with no apparent decrease between the RRs for use during the 1960s, 1970s, and 1980s, despite higher oestrogen doses in pills used in the early years. However, the reduction in risk associated with ever having used oral contraceptives differed by tumour type, being stronger for carcinomas (RR 0·69, 95% CI 0·66-0·71) than sarcomas (0·83, 0·67-1·04; case-case comparison: p=0·02). In high-income countries, 10 years use of oral contraceptives was estimated to reduce the absolute risk of endometrial cancer arising before age 75 years from 2·3 to 1·3 per 100 women. INTERPRETATION Use of oral contraceptives confers long-term protection against endometrial cancer. These results suggest that, in developed countries, about 400 000 cases of endometrial cancer before the age of 75 years have been prevented over the past 50 years (1965-2014) by oral contraceptives, including 200 000 in the past decade (2005-14). FUNDING Medical Research Council, Cancer Research UK.

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.

Postmenopausal endometrial cancer risk and body size in early life and middle age: prospective cohort study.

Background:Greater adiposity in early life has been linked to increased endometrial cancer risk in later life, but the extent to which this association is mediated through adiposity in later life is unclear.Methods:Among postmenopausal women who had never used menopausal hormone therapies and reported not having had a hysterectomy, adjusted relative risks (RRs) of endometrial cancer were estimated using Cox regression.Results:Among 249 791 postmenopausal women with 7.3 years of follow-up on average (1.8 million person-years), endometrial cancer risk (n=1410 cases) was strongly associated with current body mass index (BMI) at baseline (RR=1.87 per 5 kg m−2 increase in BMI, 95% confidence interval (CI): 1.77–1.96). Compared with women thinner than average at age 10, the increased risk among women plumper at age 10 (RR=1.27, 95% CI: 1.09–1.49) disappeared after adjustment for current BMI (RR=0.90, 95% CI: 0.77–1.06). Similarly, compared with women with clothes size 12 or less at age 20, the increased risk among women with clothes size 16 or larger (RR=1.87, 95% CI: 1.61–2.18) was not significant after adjustment for current BMI (RR=1.03, 95% CI: 0.88–1.22).Conclusion:Among women who have never used hormone therapy for menopause, the association between body size in early life and endometrial cancer risk in postmenopausal women can be largely explained by women’s current BMI.

Smoking, Surgery, and Venous Thromboembolism Risk in Women United Kingdom Cohort Study

Background— Evidence about the effect of smoking on venous thromboembolism risk, generally and in the postoperative period, is limited and inconsistent. We examined the incidence of venous thromboembolism in relation to smoking habits, both in the absence of surgery and in the first 12 postoperative weeks, in a large prospective study of women in the United Kingdom. Methods and Results— During 6 years’ follow-up of 1 162 718 women (mean age 56 years), 4630 were admitted to hospital for or died of venous thromboembolism. In the absence of surgery, current smokers had a significantly increased incidence of venous thromboembolism compared with never-smokers (adjusted relative risk 1.38, 95% confidence interval 1.28–1.48), with significantly greater risks in heavier than lighter smokers (relative risks 1.47 [95% confidence interval 1.34–1.62] and 1.29 [95% confidence interval 1.17–1.42] for ≥15 versus <15 cigarettes per day). Current smokers were also more likely to have surgery than never-smokers (relative risk 1.12, 95% confidence interval 1.12–1.13). Among women who had surgery, the incidence of venous thromboembolism in the first 12 postoperative weeks was significantly greater in current than never-smokers (relative risk 1.16, 95% confidence interval 1.02–1.30). Conclusions— Venous thromboembolism incidence was increased in current smokers, both in the absence of surgery and in the 12 weeks after surgery. Smoking is another factor to consider in the assessment of venous thromboembolism risk in patients undergoing surgery.

Antidepressants, Depression, and Venous Thromboembolism Risk: Large Prospective Study of UK Women

Background Some investigators have reported an excess risk of venous thromboembolism (VTE) associated with depression and with use of antidepressant drugs. We explored these associations in a large prospective study of UK women. Methods and Results The Million Women Study recruited 1.3 million women through the National Health Service Breast Screening Programme in England and Scotland. Three years after recruitment, women were sent a second questionnaire that enquired about depression and regular use of medications in the previous 4 weeks. The present analysis included those who responded and did not have prior VTE, cancer, or recent surgery. Follow‐up for VTE was through linkage to routinely collected National Health Service statistics. Cox regression analyses yielded adjusted hazard ratios and 95% CIs. A total of 734 092 women (mean age 59.9 years) were included in the analysis; 6.9% reported use of antidepressants, 2.7% reported use of other psychotropic drugs, and 1.8% reported being treated for depression or anxiety but not use of psychotropic drugs. During follow‐up for an average of 7.3 years, 3922 women were hospitalized for and/or died from VTE. Women who reported antidepressant use had a significantly higher risk of VTE than women who reported neither depression nor use of psychotropic drugs (hazard ratio, 1.39; 95% CI, 1.23–1.56). VTE risk was not significantly increased in women who reported being treated for depression or anxiety but no use of antidepressants or other psychotropic drugs (hazard ratio, 1.19; 95% CI, 0.95–1.49). Conclusions Use of antidepressants is common in UK women and is associated with an increased risk of VTE.

Cohort Profile: the Million Women Study.

The Million Women Study started recruiting participants over 20 years ago, in 1996. The initial stimulus was to obtain robust prospective information on the risk of breast cancer associated with use of different types of menopausal hormone therapy (HT). When planning the necessary largescale prospective study, an equally important aim was to obtain reliable information on the effects of other potentially modifiable factors that affect women’s health as they age. In the early 1990s use of HT increased rapidly in the UK and elsewhere, stimulated in part by claims that use of HT could improve general well-being and increase life expectancy. By the mid-1990s, however, worldwide evidence was beginning to show that HT preparations increased breast cancer risk, though there was little information about the effect of the type of HT most commonly used in Europe, containing both oestrogens and progestagens. It was also clear that women born in the 1940s, who reached adulthood in the 1960s, had considerably different lifestyles compared with previous generations. For example, large proportions had begun smoking and using oral contraceptives as teenagers and young adults, and the long-term effects of these behaviours could not be studied reliably until the 1990s. At the same time there was growing concern about the effects of the increasing prevalence of obesity, and claims that other factors such as diet had important effects on health, all of which required largescale prospective evidence. The UK National Health Service (NHS) provides extraordinarily efficient ways of establishing and maintaining long-term follow-up for large prospective epidemiological studies. Over 99% of the UK population, and all Million Women Study participants, are registered with the NHS, and every individual has a unique NHS number. Electronic linkage, using each individual’s NHS number, to routinely collected NHS databases provides virtually complete follow-up information about deaths, emigrations, cancer registrations and hospital admissions. The NHS Breast Screening Programme invites all UK women registered with the NHS, of a specified age, for free routine breast screening every 3 years. In 1996–2001 the programme routinely invited women aged 50–64 years for mammographic screening, by sending each individual a letter offering them a specific date and time at a specific screening centre. In 66 NHS screening centres, the Million Women Study recruitment questionnaire was included with the invitation letter for screening. Pilot studies in 1994–96 had shown that inclusion of a questionnaire with the invitation did not affect uptake of breast screening. The coordinating centre for the Million Women Study is based in the Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford.

Smoking, Surgery, and Venous Thromboembolism Risk in Women: UK Cohort Study

Background— Evidence about the effect of smoking on venous thromboembolism risk, generally and in the postoperative period, is limited and inconsistent. We examined the incidence of venous thromboembolism in relation to smoking habits, both in the absence of surgery and in the first 12 postoperative weeks, in a large prospective study of women in the United Kingdom. Methods and Results— During 6 years’ follow-up of 1 162 718 women (mean age 56 years), 4630 were admitted to hospital for or died of venous thromboembolism. In the absence of surgery, current smokers had a significantly increased incidence of venous thromboembolism compared with never-smokers (adjusted relative risk 1.38, 95% confidence interval 1.28–1.48), with significantly greater risks in heavier than lighter smokers (relative risks 1.47 [95% confidence interval 1.34–1.62] and 1.29 [95% confidence interval 1.17–1.42] for ≥15 versus <15 cigarettes per day). Current smokers were also more likely to have surgery than never-smokers (relative risk 1.12, 95% confidence interval 1.12–1.13). Among women who had surgery, the incidence of venous thromboembolism in the first 12 postoperative weeks was significantly greater in current than never-smokers (relative risk 1.16, 95% confidence interval 1.02–1.30). Conclusions— Venous thromboembolism incidence was increased in current smokers, both in the absence of surgery and in the 12 weeks after surgery. Smoking is another factor to consider in the assessment of venous thromboembolism risk in patients undergoing surgery.