Oral Contraception Study Research Articles

Oral contraception and other factors in relation to hospital referral for fracture: Findings in a large cohort study

There is good evidence that estrogens and progestogens have an important effect on bone metabolism. This article explores the relationship between oral contraceptive (OC) use and fractures occurring at various sites among the 17,032 participants in the Oxford-Family Planning Association contraceptive study, which now includes information accumulated during 310,000 woman-years of observation between 1968 and 1994. In total, 1308 women suffered at least one fracture during the follow-up period, which was largely confined to premenopausal years. When all fractures were combined, there was a modest, but highly significant trend (p <0.001) of increasing risk with total duration of oral contraceptive use. In addition, there was statistically significant heterogeneity (p <0.01) when overall fracture rates were examined in relation to recency of oral contraceptive use during the premenopausal lifespan. The highest relative risk (1.3, 95% CI 1.1–1.5) was for current or recent oral contraceptive users; however, viewed as a whole, no clear pattern of risk was apparent. Examination of the data for individual fracture sites (including the lower end of the radius/ulna) did not provide any evidence of a protective effect of oral contraceptive use. These results are closely similar to those reported from the Royal College of General Practitioners Oral Contraception Study in 1993.

Epidemiology of oral contraceptives and cardiovascular disease.

To review the association between combined oral contraceptives and cardiovascular disease, with emphasis on oral contraceptives containing low doses of estrogen (low-dose oral contraceptives). A systematic search of the MEDLINE database was done for all relevant articles published between 1967 (when low-dose oral contraceptives were introduced in the United States) and June 1997. Textbooks, meeting proceedings, and reference lists were also searched. All English-language human epidemiology studies of oral contraceptives that used cardiovascular disease as an end point were reviewed. Animal and metabolic studies were reviewed only if they were especially relevant to the mechanism of action of oral contraceptives. Descriptive and analytic data from each study were collected. Data were organized by cardiovascular end point, study design, estrogen dose, and type of progestogen. Data on relative and absolute risk are presented to address current prescription guidelines. The risk for cardiovascular disease is lower with current preparations of oral contraceptives, including those that contain the new progestogens, than with older oral contraceptives containing high doses of estrogen. Among users of low-dose oral contraceptives, cardiovascular diseases occur mainly in smokers and women with predisposing factors. Every effort should be made to encourage smoking cessation among potential users of oral contraceptives.

Increased Risk of Mental Illness and Suicide in Oral Contraceptive and Hormone Replacement Therapy Studies

Epidemiological studies find that takers of contraceptive or menopausal steroid sex hormones are at increased risk of suicide and mental illness. In spite of omitting women from the UK Hormone Replacement Therapy Study who discontinued therapy within the first 12 months, the relative risk (RR) of suicide and suspected suicide was reported as 2.4. In the Royal College of General Practitioners' Oral Contraceptive Study, neurotic depression was the commonest reason for discontinuing hormones, and RRs for attempted suicide for current and former users were 1.42 and 2.12 respectively. In the Oxford/Family Planning Association Contraception Study, first-event hospital admission rates for selfpoisoning were 0.83/1000 women years for oral contraceptive users but only 0.21 for diaphragm users. In the Walnut Creek Contraceptive Drug Study, RRs for current users were 3.2 for depressive neurosis and 2.0 for psychosis. The fact that mood and behaviour changes may be side-effects of taking hormones should be considered much more frequently. These changes may be immediate or occur insidiously over a period of time. Significant 'knock-on' effects for family life and society in general are possible. Hormones can cause changes in mineral and vitamin status which are associated with mental illness.

A Methodological Review of the Royal College of General Practitioners' Oral Contraception Study

The Royal College of General Practitioners' Oral Contraception Study, started in 1968/9, is reviewed. The limitations of any cohort study and the particular characteristics of this study mean that only large effects on common diseases are likely to be detected. Effects on conditions that might be subject to reporting bias, and on those, like cancers, which may only appear after a long time lag, are particularly unlikely to be estimated with any accuracy. The study does show a clear connection between oral contraceptive use and cardiovascular disease. It also suggests a range of conditions, including depression and some cancers, whose incidence might be increased by oral contraceptive use, and a few whose incidence might be decreased.

Case-control study of oral contraceptives and risk of thromboembolic stroke: results from international study on oral contraceptives and health of young women

Objective: To determine the influence of oral contraceptives (particularly those containing modern progestins) on the risk for ischaemic stroke in women aged 16–44 years.Design: Matched case-control study.Setting: 16 centres in...

Combined oral contraceptives and liver disease

Although some information is available about the risk of liver tumors associated with combined oral contraceptive use, little is known about the relationship with other hepatic problems. Data from two large long-term observational studies, the Royal College of General Practitioners' (RCGP) Oral Contraception Study and the Oxford-Family Planning Association (Oxford-FPA) Study, were used to examine this issue. Observations accumulated over a period of up to 27 years were available for each study. The incidence of liver disease in each study was low. There was no evidence of an increased risk of serious liver disease overall among current or former pill users. The RCGP study found a modest increased risk of mild liver disease associated with oral contraceptive use which declined after four years of use and after cessation of use. This increased risk occurred in women who had used oral contraceptives containing more than 50 μg of estrogen.

Prevalence and characteristics associated with use of hormone replacement therapy in Britain.

To describe trends in the prevalence of hormone replacement therapy (HRT) use among women living in Britain between 1981 and 1990, and to determine whether women who receive HRT are different from those who do not. Population-based, prospective, observational study. Fourteen hundred general practices throughout the United Kingdom contributing data to the Oral Contraception Study of the Royal College of General Practitioners (RCGP). Prevalence of use: women still under general practitioner observation in the Oral Contraception Study at the end of December 1981 (n = 19,949), 1984 (n = 18,037), 1987 (n = 16,063), 1990 (n = 13,379). Characteristics of users: 3806 HRT users and 3806 never-users matched for age, hysterectomy status and duration of observation in the Oral Contraception Study. Ever-use of hormone replacement therapy. Between 1981 and 1990 there was a threefold increase in HRT use among women both among those who had and those who had not had a hysterectomy. Increasing trends were apparent in all age groups. By December 1990, 19% of all women (36% of those who had had a hysterectomy and 16% of those who had not had a hysterectomy) had ever used HRT; 9% were classified as current users. Forty-one percent of women using HRT who had had a hysterectomy received combined (oestrogen and progestogen) preparations; 31% of those who had not had a hysterectomy received at least one prescription for unopposed oestrogen. Among those who had had a hysterectomy, HRT was more likely to be prescribed in women with a history of smoking, nonpsychotic psychiatric illness, hot flushes, other menopausal symptoms, oophorectomy, migraine or headache. Women with breast cancer were less likely to receive HRT. In women who had not had a hysterectomy, smoking, nonpsychotic psychiatric illness, hot flushes, other menopausal symptoms, migraine, headache and previous use of oral contraceptives increased the chances of HRT being used; a history of breast cancer, ischaemic heart disease or diabetes mellitus reduced the chances. Weaker associations of reduced risk were also found for hypertension and lower social class. The influence of hot flushes and other menopausal symptoms appeared to be stronger in women who used HRT before the age of 50, than in older women. HRT use increased dramatically within the cohort during the nine year period. HRT users are different from nonusers in a number of ways which could have opposing effects on a woman's risk of cardiovascular disease.

A prospective study of oral contraceptives and NIDDM among U.S. women.

To examine prospectively the association between modern oral contraceptives with low doses of estrogen and progestin and subsequent incidence of NIDDM. In a prospective cohort study, 98,590 U.S. female nurses aged 25 to 42 and free of diagnosed diabetes, coronary heart disease, stroke, and cancer at baseline in 1989 were followed for 4 years. Endpoint was incidence of confirmed NIDDM. Oral contraceptive use was reported on mailed questionnaires. During 352,067 person-years follow-up, we confirmed 185 incident cases of NIDDM. After adjusting for age, BMI, cigarette smoking, family history of diabetes, parity, physical activity, alcohol intake, ethnicity, history of diagnosis of infertility, elevated cholesterol, and hypertension, women currently using oral contraceptives had a relative risk (RR) of 1.6 (95% CI, 0.9-3.1). For past users, the multivariate RR was 1.2 (95% CI, 0.8-1.8). This association was attenuated after restricting the analysis to symptomatic cases of NIDDM. For current users, RR = 1.3 (95% CI, 0.6-2.8), and for past users, RR = 0.9 (95% CI, 0.6-1.4), suggesting that increased surveillance may explain at least part of any excess risk. In this large prospective study, we found no appreciable increase in the 4-year risk of NIDDM among current users of oral contraceptives. There was no apparent increase in risk among past users. The small number of cases reflect the low absolute risk of NIDDM in this population of young women.

Cardiovascular sequelae of toxaemia of pregnancy.

OBJECTIVE: To determine whether the rate of cardiovascular disease is different among parous women with a general practitioner reported history of toxaemia of pregnancy than among those not reported to...

Use of exogenous hormones and risk of temporomandibular disorder pain

Temporomandibular disorders (TMD) are common pain conditions that have their highest prevalence among women of reproductive age. The higher prevalence of TMD pain among women, pattern of onset after puberty and lowered prevalence rates in the post-menopausal years suggest that female reproductive hormones may play an etiologic role in TMD. Two epidemiologic studies were designed to assess whether use of exogenous hormones is associated with increased risk of TMD pain. Both used data from automated pharmacy records of women enrolled in a large health maintenance organization to identify prescriptions filled for post-menopausal hormone replacement therapies (Study 1) or for oral contraceptives (OCs) (Study 2). Study 1 employed an age-matched case-control design to compare post-menopausal hormone use among 1291 women over age 40 referred for TMD treatment and 5164 controls not referred. After controlling for health services use, the odds of being a TMD case were approximately 30% higher among those receiving estrogen compared to those not exposed ( P=0.002); a clear dose-response relationship was evident. The relationship of progestin use to TMD was not statistically significant. Study 2 used a similar design to examine the relationship of OC use to referral for TMD care, drawing on data from 1473 cases and 5892 controls aged 15–35. Use of OCs was also associated with referral for TMD care, with an increased risk of TMD of approximately 20% for OC users, after controlling for health services use ( P<0.05). These results suggest that female reproductive hormones may play an etiologic role in orofacial pain. This relationship warrants further investigation through epidemiologic, clinical and basic research.

Reliability of data from proxy respondents in an international case-control study of cardiovascular disease and oral contraceptives. World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.

To evaluate the reliability of data supplied in a case-control study by proxy respondents for cases who were too ill to do so themselves. A hospital based, case-control study of the current use of oral contraceptives (OC) and cardiovascular diseases. Data from "true" controls matched to a subset of cases were compared with those supplied by proxy respondents about the true controls. Hospitals in 21 centres from Africa, Asia, Europe, and Latin America. For a subset of cases, 403 pairs of controls-one "true" and one proxy-were interviewed. "True" controls were matched by age, place, and time of admission and were admitted with 1 of 27 permissible diagnoses not associated with OC use. Proxy controls were either relatives or friends of true controls. Levels of concordance between data from proxy and true controls were high for most variables regarding recent events, including current OC use, but were greatly diminished when detailed information, particularly from the past, was required. Husbands were usually the best proxy, although this was question-specific. The sensitivity and specificity of proxy responses were 93% (95% confidence intervals: 77%, 99%) and 100% (98%, 100%) respectively, for current use of OC. Assuming the misclassification of current OC use by proxy cases is similar to that produced by proxy controls, the estimated impact of using proxy data on risk estimates associated with current OC use was to bias the overall estimate of risk of stroke by less than 3% and the risks of both acute myocardial infarction and venous thromboembolism by less than 1%. Friends or relatives, and particularly husbands, provided reliable information when used as proxy respondents for young women. The estimated impact of misclassification by proxy respondents on overall risk estimates in the WHO collaborative study was less than that which would have arisen if information from proxy respondents had not been used.

Rebuilding confidence in oral contraceptives: a new imperative in family planning.

On December 14, 1995, the first public presentation of results of the Transnational Case-Control Study of Oral Contraceptives and the Health of Young Women was made at the winter meeting of the British Pharmacological Society at Brighton. Four weeks later, those results and further analyses were published in the British Medical Journal. There has been much debate about them in Europe and elsewhere. I feel privileged to have been invited to write a Leading Article about the safety of combined oral contraceptives in the British Journal of Clinical Pharmacology. These are personal opinions about the meaning of all the recent pharmacoepidemiological findings. With an historical context as the background I have added my personal reflections as a scientist and a public health doctor. These views do not necessarily reflect the views of my co-investigators.

Routine screening for coagulation inhibitors prior to prescribing the pill: Prevalence data from a large cohort of German pill starters

A total of 2674 women were recruited to participate in a multicenter oral contraceptive (OC) study on hemostasis. At baseline, protein S activity less than 60% of normal values was found in two volunteers (0.75 per 1000) and the antithrombin III activity was less than 60% of normal values in three volunteers (1.1 per 1000). All measurements were confirmed by a second assessment. In contrast, of the 28 women presenting with protein C levels less than 60% of normal values, only six were confirmed (2.3 per 1000). Of these, one was also protein S-deficient. Seven women could not be studied twice and 15 were false-low according to their normal control values. These data suggest that routine screening of the hemostatic system may reveal findings suggestive of inhibitor deficiencies in as many as 3.75 per 1000 of apparently healthy candidates for OCs. However, our data also demonstrate that unselected screening is compromised by a considerable rate of false-positive results and cannot generally be recommended. However, screening of coagulation inhibitors is feasible in women with a family history of thromboembolic disease.

Prospective study of oral contraceptives and hypertension among women in the United States.

Oral contraceptives induce hypertension in approximately 5% of users of high-dose pills that contain at least 50 micrograms estrogen and 1 to 4 mg progestin, and small increases in blood pressure have been reported even among users of modern low-dose formulations. However, neither the responsible hormone in the oral contraceptive nor particular subgroups of women who might be susceptible to the hypertensive effect of oral contraceptives have been identified. In a prospective cohort study in the United States, 68 297 female nurses aged 25 to 42 years and free of diagnosed hypertension, diabetes, coronary heart disease, stroke, and cancer at baseline were followed up for 4 years. During 231 006 person-years of follow-up, 1567 incident cases of hypertension were diagnosed. Compared with women who had never used oral contraceptives, the age-adjusted relative risk was 1.5 (95% CI = 1.2 to 1.8) for current use and 1.1 (95% CI = 0.9 to 1.2) for past use. After adjustment for age, body mass index, hormones cigarette smoking, family history of hypertension, parity, physical activity, alcohol intake, and ethnicity, current users of oral contraceptives had an increased risk of development of hypertension (RR = 1.8; 95% CI = 1.5 to 2.3) compared with women who had never used them. The multivariate relative risk for past users was 1.2 (95% CI = 1.0 to 1.4). There were no important modifying effects of age, family history of hypertension, ethnicity, or body mass index. Current users of oral contraceptives had a significant, moderately increased risk of hypertension. However, among this group, only 41.5 cases per 10 000 person-years could be attributed to oral contraceptive use. Risk decreased quickly with cessation of oral contraceptives, and past users appeared to have only a slightly increased risk.

Interim review of the Transnational Case-control Study of Oral Contraceptives and Health: approved protocol revisions through September 1995.

The protocol of the Transnational Study on Oral Contraceptives has been published at the outset of the study in order to ensure the correct performance of the study and to ensure the study's scientific integrity. Potential revisions and additions to this protocol had been announced in the prior publication. This article focuses on those points of protocol which have been resolved as practical experience was gathered as well as additional modifications required by practical and scientific considerations. The major alterations are based on exposure prevalences in controls and on power calculations. The low (1.8%) exposure to gestodene among German controls led to the discontinuation of the German component and to the accelerated accession in additional countries. control ratio was altered to 3:1 for purposes of economy based on power calculations. Numerous minor points, most addressed in the prior protocol, have been resolved. It is found that these modifications of the study protocol do not impair the study's conduct, its scientific integrity, nor its capability of providing answers to the study question.

Third generation oral contraceptive pills

Is the scare over the increased risk of thrombosis justified? Britain's Committee on Safety of Medicines has issued a recommendation that combined oral contraceptives containing the so called third generation progestogens, desogestrel and gestodene, should no longer be routinely prescribed. The committee came to this conclusion after examining the data from three unpublished studies, two of which have not been completed. These studies--an international study organised by the World Health Organisation; the European transnational study of oral contraceptives, which is funded by the pharmaceutical company Schering AG; and a study of data from the United Kingdom general practice research database (formerly known as VAMP)--were designed to examine whether the risk of vascular disease in women taking the newer oral contraceptive pills differed from that in women taking the slightly older pills containing predominantly the progestogen levonorgestrel. …

Cervical Intraepithelial Neoplasia in Jordan: A Ten Year Retrospective Cytoepidemiologic Study

Occurrence of cervical intraepithelial neoplasia (CIN) was studied in 10,659 females attending obstetric and gynecology clinics in Jordan. The frequency rate of intraepithelial neoplasia was 1.1% in 7743 Jordanian females and 2916 non-Jordanian residents of younger age during the period from 1982 to 1991 inclusive. The incidence rate in 2649 Jordanian females, selected because they attended only for routine checkup, was 49 per 100,000. There were 121 CIN cases which were graded into Grade I (21%), II (48%) and III (31%) respectively. Histological grading correlated with cytology in 70% of the cases while in the remaining 30%, cytologic underrating by one grade was noted; evidence against any overdiagnosis of CIN in our series. Study of the human papillomavirus (HPV) was outside the scope of this effort. However, circumcision in male partners and marital status were associated with a lower frequency of CIN. Age at marriage and average duration, parity, breast feeding, the contraceptive pill, socioeconomic status and menstrual disorders showed no relationship to the frequency of CIN in our patients. Any differences in the latter between Jordanian and non-Jordanian females are believed due to cultural factors. Conization in 27 cases proved effective at 30 months' follow-up. Occurrence of CIN in Jordanian females appears substantial although much lower than that seen in high incidence zones, while its incidence in the general female population remains to be determined. This study shows for the first time the value of Papanicolaou (Pap) smears in Jordanian females over 20 years of age with special emphasis on those over 35 years of age attending obstetric and gynecology clinics.

Today's oral contraceptives

The most important established adverse events associated with use of oral contraceptives are the cardiovascular ones. Many studies have shown that women have an increased risk of numerous vascular conditions while they use the contraceptive pill. There is little epidemiological evidence to support the hypothesis that this risk persists once the pill is stopped. The Royal College of General Practitioners' (RCGP) Oral Contraception Study has observed an elevated risk of stroke among former users of the pill but this effect seems to diminish with time. Smoking appears greatly to exacerbate the vascular effects of oral contraceptives. Important medical benefits associated with oral contraceptive use include a substantial, persistent protection against endometrial and ovarian cancer. Currently available mortality data suggest that these benefits counterbalance the adverse effects.

Oral contraception and stroke. Evidence from the Royal College of General Practitioners' Oral Contraception Study.

A nested case-control analysis of data collected during the prospective Royal College of General Practitioners' Oral Contraception Study was performed to examine the relation between use of oral contraception and risk of stroke. The 253 women who had a first-ever stroke (International Classification of Diseases, eighth revision, codes 4300 to 4389) or amaurosis fugax (code 3791) between 1968 and 1990 (case subjects) were compared with 759 women who did not have this diagnosis (control subjects). Smoking, social class, and history of hypertension were found to be important risk factors for stroke. Women who had ever used oral contraceptives had an increased risk of all stroke (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.0, adjusted for smoking and social class) and of a fatal event (adjusted odds ratio, 2.3; 95% confidence interval, 1.2 to 4.4). A significant doubling of all stroke risk was observed among current users, an effect that was apparent in both smokers and nonsmokers. Former users had a small nonsignificant elevation in risk of all stroke but a stronger risk of a fatal event. The effects in former users appeared to be restricted to women who smoked. Current users of oral contraceptives appeared to be at increased risk of stroke. There is some evidence that former users may also have a persisting effect, although further research is needed to confirm these observations.

Cigarette smoking and parity as risk factors for the development of symptomatic gall bladder disease in women: results of the Royal College of General Practitioners' oral contraception study.

The effects of cigarette smoking and parity on the development of symptomatic gall bladder disease remain controversial. These relations have been examined in a cohort of 46,000 women followed for up to 19 years during the Royal College of General Practitioners' (RCGP) oral contraception study. During follow up, 1087 women were recorded as experiencing their first ever episode of symptomatic cholelithiasis (International Classification of Diseases, 8th revision (ICD-8) 574) or cholecystitis (ICD-8 575). Smokers were more likely to develop symptomatic gall bladder disease than non-smokers (relative risk 1.19; 95% confidence intervals (95% CI) 1.06 to 1.34) and there was a significant trend with the number of cigarettes smoked daily (test for trend chi 2 = 7.58, p < 0.01). This relation was most apparent among never users of oral contraceptives, although similar trends were found among current and former users. A significant direct relation between symptomatic gall bladder disease and parity was also found (test for trend chi 2 = 21.89, p < 0.001). When all were examined together a trend of increasing risk with lower social class was also found (test for trend chi 2 = 5.72, p = 0.02). Current users of oral contraceptives had a moderately increased risk of symptomatic gall bladder disease (relative risk 1.15; 95% CI 0.99 to 1.34), unlike former users (relative risk 1.03; 95% CI 0.90 to 1.18). These results suggest that smoking and parity are important risk factors for the development of symptomatic gall bladder disease in women.