Oral contraceptive use and cancer: final report from the Oxford-Family Planning Association contraceptive study.

BACKGROUND: This analysis provides the final results on cancer incidence in relation to oral contraceptive (OC) use from the Oxford-Family Planning Association (Oxford-FPA) contraceptive study, which closed at the end of 2010. An additional 6 years of observation have been added since our last report and there has been an increase in the numbers of cancers of over 50% at seven of the sites considered. STUDY DESIGN: The Oxford-FPA study includes 17032 women aged 25-39 years recruited from 1968 to 1974 at contraceptive clinics in England and Scotland. These women were using OCs, a diaphragm or an intrauterine device. Information about cancer incidence among them has been collected from recruitment until closure of the study. RESULTS: OC use was not related to nonreproductive cancer. Breast cancer findings (1087 cases) were entirely negative; the rate ratio (RR) comparing ever users of OCs with never users was 1.0 [95% confidence interval (CI): 0.9-1.1]. Only two cases of cervical cancer have been added since our last report (total: 61 cases); the RR comparing ever use with never use is now 3.4 (95% CI: 1.6-8.9). The risk of this disease increases sharply with duration of OC use and declines steadily with interval since last OC use. OC use protects against both uterine body cancer (124 cases) and ovarian cancer (143 cases). The RRs comparing ever use with never use were 0.5 (95% CI: 0.3-0.7) and 0.5 (95% CI: 0.4-0.7), respectively. Protection against both these cancers increased with duration of OC use and waned with interval since last use, but an effect was still present 28 or more years after discontinuation. CONCLUSIONS: In our study, OC use had no effect on nonreproductive cancers or on breast cancer. The risk of cervical cancer was increased and that of uterine body cancer and ovarian cancer was decreased by OC use. All these effects increased with duration of use and declined with interval since last use. The beneficial effects of OC use on cancer outweighed the adverse effects. These findings should reassure older women who used OCs in the past.

Factors affecting mortality in a large cohort study with special reference to oral contraceptive use.

BACKGROUND: This analysis updates mortality in the Oxford-Family Planning Association (Oxford-FPA) contraceptive study, with emphasis on oral contraceptive (OC) use. STUDY DESIGN: The Oxford-FPA study includes 17,032 women recruited from 1968-1974 at contraceptive clinics, aged 25-39 years, using OCs a diaphragm or an intrauterine device. Follow-up has been to March 2009; by then, 1715 women had died. RESULTS: The rate ratio (RR) for overall mortality was 0.87 (CI 0.79-0.96), comparing ever-users of OCs with never-users. The RR for fatal cervical cancer was increased (7.3), but the CIs were very wide (1.2-305). There was no association between ever-use of OCs and mortality from breast cancer (RR 1.0, CI 0.8-1.2), nor was fatal breast cancer related to duration of OC use. OC use strongly protected against death from other uterine cancer and ovarian cancer; RRs for ever-use of OCs were 0.3 (CI 0.1-0.8) and 0.4 (CI 0.3-0.6), respectively. Protection increased with duration of OC use and persisted more than 20 years after cessation. Circulatory disease mortality was not increased, the RR for ever-use of OCs being 0.9 (CI 0.7-1.1). The overall mortality RR for all women smoking 15+ cigarettes daily was 2.25 (CI 1.99-2.53) and, for all women with a body mass index of 28+ kg/m(2), was 1.33 (CI 1.07-1.64). CONCLUSIONS: Long-term follow-up strongly suggests that OC use slightly reduces all cause mortality.

Some minor female reproductive system disorders: findings in the Oxford-Family Planning Association contraceptive study.

BACKGROUND: The Oxford-Family Planning Association (Oxford-FPA) contraceptive study has provided information on many serious diseases of the female reproductive tract. No information has been published about a number of common minor conditions. This report fills the gap with regard to uterine polyp, cervicitis, cervical erosion, and vaginitis and vulvitis. METHODS: The Oxford-FPA study includes 17 032 married women recruited at ages 25-39 years between 1968 and 1974 from clinics in England and Scotland. These women were followed up until mid-1994. Information collected during follow-up included details of contraceptive use, cervical smears taken at the clinic, pregnancies and hospital referrals. RESULTS: Oral contraceptive (OC) use was associated with a reduction in first hospital referral for uterine polyp and for vaginitis and vulvitis, which became more marked with increasing duration of use. There was a slightly increased rate of hospital referral for cervicitis in OC users. Referral for cervical erosion was markedly increased in current and recent OC users (rate ratio 2.1, 95% confidence interval 1.8-2.4). This increase in risk steadily declined after OC use was discontinued. First hospital referral for both uterine polyp and cervical erosion showed a highly significant negative association with numbers of cigarettes smoked per day. The explanation for these observations is unknown. CONCLUSIONS: It should be remembered that the OCs studied were mainly those used in the 1970s and 1980s and mostly contained 50 microg estrogen. On balance, the overall effect of OC use on the conditions considered was neutral or beneficial. The apparent protective effect of cigarette smoking against uterine polyp and cervical erosion, even if valid, counts as nothing against the overwhelming adverse effects of smoking on health.

Oral contraceptives and benign breast disease: an update of findings in a large cohort study.

BACKGROUND: This report is an update of findings, first reported in 1981, on the relationship between oral contraceptives (OCs) and benign breast disease with special reference to OCs containing <50 mcg estrogen. STUDY DESIGN: The Oxford-Family Planning Association study includes 17,032 women using different methods of contraception recruited at 17 family planning clinics between 1968 and 1974. These women were subsequently followed up until mid-1994. Among other items, information about contraceptive method changes and morbidity as measured by hospital referrals was collected during follow-up. RESULTS: The findings in the present analysis were broadly similar to those reported in 1981, but based on much larger numbers of cases [fibroadenoma (FA), 185 cases; chronic cystic disease (CCD), 1361 cases; breast lump with no specific diagnosis (BL), 650 cases]. Hospital referral rates for FA and CCD (but not BL) declined with increasing duration of OC use, with the effect being strongest among recent users. The apparent protective effect was present for women using OCs containing >50 mcg, 50 mcg and <50 mcg estrogen but not for progestogen-only OCs. CONCLUSION: Low-dose combined OCs containing <50 mcg estrogen appear to reduce the risk of hospitalization for FA and CCD as well as older preparations containing higher doses of estrogen.

Pregnancy outcome among twins conceived after subfertility treatment compared with natural twins: A population-based study.

Pregnancy outcome and characteristics of women who conceive following subfertility treatment remains a subject of great interest. We analyzed these variables among 199 women who delivered a registerable twin birth compared with 1773 women who delivered a naturally conceived twin birth in a population-based obstetric cohort drawn from around Oxford, England. Treatment was restricted to conceptions involving simple ovulation induction only. Treated mothers were of significantly higher social class and older, more likely to deliver girls and to be delivered by cesarean section, and significantly less likely to be smokers at the time of antenatal booking and to have delivered previous pregnancies. Pregnancy outcome was similar between the two groups for most measures, with the exception of birthweight which was lower in treated twins, though not significantly so. Overall the results are reassuring with respect to outcome in twin pregnancies following simple ovulation induction.

Effect of testing for human papillomavirus as a triage during screening for cervical cancer: observational before and after study.

OBJECTIVE: To assess the effect of introducing testing for human papillomavirus combined with liquid based cytology in women with low grade cytological abnormalities. DESIGN: Observational before and after study. SETTING: Three cervical screening laboratories, England. PARTICIPANTS: 5654 women aged 20-64 with low grade cytological abnormalities found at routine cervical screening in a pilot; 5254 similar women in the period before the pilot. INTERVENTIONS: Human papillomavirus testing combined with liquid based cytology in the management of women with borderline or mildly dyskaryotic cervical smear results compared with conventional smear tests, with immediate referral to colposcopy of women positive for human papillomavirus. RESULTS: 57.9% (3187/5506) of women tested in the pilot were positive for human papillomavirus. The rate of repeat smears fell by 74%, but the rate of referral to colposcopy for low grade cytological abnormalities more than doubled. The estimated negative predictive value of human papillomavirus testing varied between 93.8% and 99.7%. CONCLUSION: The addition of testing for human papillomavirus in women with low grade cytological abnormalities resulted in a reduction in the rate of repeat smears, but an increase in rates of referral to colposcopy.

Mortality in relation to oral contraceptive use and cigarette smoking.

BACKGROUND: As part of the Oxford Family Planning Association study, we compared mortality in relation to oral contraceptive use and smoking to highlight the differences between them from the perspective of public health. METHODS: The study consisted of 17032 women, aged 25-39 years at entry, recruited between May 1, 1968, and July 31, 1974, who had used oral contraceptives, a diaphragm, or an intrauterine device. We assessed mortality from follow-up data recorded until Dec 31, 2000. The analysis is based on woman-years of observation. FINDINGS: We analysed 889 deaths. Women who had ever used oral contraceptives had increased mortality from cervical cancer (rate ratio 7.2, 95% CI 1.1-303), and decreased mortality from other uterine (0.2, 0.0-0.8) and ovarian cancers (0.4, 0.2-0.7). Oral contraceptives had some adverse effect on deaths from ischaemic heart disease in women who smoked 15 or more cigarettes per day. For all causes of mortality, the rate ratio for death in women who ever used oral contraceptives was 0.89 (95% CI 0.77-1.02). By contrast, this rate ratio was 1.24 (1.03-1.49) in those who smoked one to 14 cigarettes per day, and 2.14 (1.81-2.53) in those who smoked 15 or more cigarettes per day. INTERPRETATION: There was no harmful effect of oral contraceptive use on overall mortality. By contrast, death from all causes was more than twice as high in smokers of 15 or more cigarettes a day as in non-smokers. The harmful effect was already apparent in women aged 35-44 years.

Oral contraception and epilepsy: findings in a large cohort study.

There is no good evidence that oral contraceptives (OCs) increase the risk of epilepsy in unaffected women or increase the frequency of seizures in those suffering from the disorder. Nonetheless, manufacturers' literature continues to include warnings about OCs and epilepsy. We have analyzed the available data about epilepsy in the Oxford-Family Planning Association contraceptive study that includes 17,032 women followed for periods of up to 26 years. In total, 82 women (with no record of having suffered epilepsy when recruited to the study) were referred to hospital for diagnosis or treatment of epilepsy during the follow-up period. No association was found between OC use and the occurrence of the condition. Referral to hospital was, however, more frequent in women of low social class and in those with a high body mass index.

Effect on endometrium of long term treatment with continuous combined oestrogen-progestogen replacement therapy: follow up study.

OBJECTIVE: To determine effects of five years of treatment with an oral continuous combined regimen of 2 mg 17beta-oestradiol and 1 mg norethisterone acetate on endometrial histology in postmenopausal women. DESIGN: Follow up study in postmenopausal women. SETTING: 31 menopause clinics in the United Kingdom. PARTICIPANTS: 534 postmenopausal women, all with an intact uterus, who had completed nine months of treatment with oral continuous combined 2 mg 17beta-oestradiol and 1 mg norethisterone acetate agreed to take part in a long term follow up study. Women were assigned to different groups on the basis of the treatment status immediately before entering the original study: 360 women had taken sequential oestrogen-progestogen hormone replacement therapy, 164 had taken no hormone replacement therapy, and 10 had taken unopposed oestrogen therapy. METHODS: Endometrial aspiration specimens were taken before the women started the continuous combined regimen, after 9 and 24-36 months, and at the end of the five year treatment period or on withdrawal from the study. MAIN OUTCOME MEASURE: Results of endometrial histology. RESULTS: The duration of treatment with continuous combined hormone replacement therapy was 4.4 (range 1.1-5.9) years. Data on endometrial specimens were available for 526 women after nine months of treatment, 465 women after 24-36 months of treatment, and 398 women who completed the five years treatment (345 women) or were withdrawn between the two latter visits for biopsies (53 women). No cases of endometrial hyperplasia or malignancy were detected at biopsy; 69% of women had an endometrium classified as atrophic or unassessable on completion of the study or withdrawal from it. Before the continuous combined therapy was started, complex hyperplasia was detected in 21 women who had taken sequential hormone replacement therapy before the study and in one who had taken unopposed oestrogen. All of these women had normal results on histological examination of endometrial tissue after nine months of treatment with continuous combined hormone replacement therapy, and hyperplasia did not recur after up to five years of treatment. CONCLUSIONS: Long term treatment (for up to five years) with continuous combined hormone replacement therapy containing oestradiol 2 mg and norethisterone 1 mg daily was associated with neither endometrial hyperplasia nor malignancy. In women who had complex hyperplasia during previous sequential or unopposed regimens, the endometrium returned to normal during treatment with continuous combined hormone replacement therapy. These findings provide reassurance about the long term safety of this continuous combined regimen in terms of the endometrium.

Contraception and unexplained abdominal pain.

OBJECTIVE: To test the hypothesis that hospital referral for unexplained abdominal pain might occur less frequently in oral contraceptive (OC) users and more frequently in intrauterine device (IUD) users than in other women. DESIGN: Prospective cohort study of 17 032 women using different methods of contraception [the Oxford-Family Planning Association (FPA) contraceptive study]. OUTCOME MEASURE: Referral to hospital for unexplained abdominal pain (including pelvic pain) coded to ICD rubric 785.5 in the 8th Revision of the ICD. RESULTS: Referral was decreased by 13% (95% CI 0%-25%) in current or recent users of OCs in comparison with non-users, a difference that just reached statistical significance. No significant difference was found in the corresponding analysis for IUD users. Past users of OCs had much the same risk of referral as non-users, but the risk of referral in past users of an IUD was increased at all intervals examined, varying from 17% (95% CI -14%-55%) 13-24 months after discontinuation to 56% (95% CI 15%-107%) 73-96 months after discontinuation. Referral was 29% (95% CI 11%-50%) higher in smokers of 15 or more cigarettes a day than in non-smokers. CONCLUSION: Referral to hospital for unexplained abdominal pain may be slightly reduced in current or recent OC users and moderately increased in past IUD users. The types of IUD used most commonly in the Oxford-FPA study are, however, no longer in current use today. Hospital referral for unexplained abdominal pain seems to be moderately increased in heavy cigarette smokers.