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Etiology

Oral contraceptive use was associated with increased risk for stroke

ACP J Club. 1994 Sept-Oct;121:55. doi:10.7326/ACPJC-1994-121-2-055


Source Citation

Hannaford PC, Croft PR, Kay CR. Oral contraception and stroke. Evidence from the Royal College of General Practitioners' Oral Contraception Study. Stroke. 1994 May;25:935-42.


Abstract

Objective

To determine the risk for stroke associated with the use of oral contraceptives.

Design

22-year nested case-control study of women in the Royal College of General Practitioners' Oral Contraception Study (RCGPOCS).

Setting

Community-based study in the United Kingdom.

Participants

253 women, aged 21 to 70 years, who had a stroke or an episode of amaurosis fugax between 1968 and 1990 were identified from the RCGPOCS database. Each participant was matched for age and time in the study with 3 control participants who had not had a stroke. Exclusion criteria were history of cerebrovascular disease or malignancy before indexing; diagnosis of hypertensive encephalopathy, vertebrobasilar insufficiency, or drop attack; and lack of information regarding social class or smoking for case patients.

Assessment of risk factors

Social class (based on the occupation of the woman's husband), parity, smoking status at time of recruitment to the RCGPOCS, oral contraceptive use, hypertension, and toxemia of pregnancy.

Main outcome measures

Rates of fatal and nonfatal stroke.

Main results

Smoking, lower social class, and a history of hypertension were each associated with increased risk for stroke. Women who had ever used oral contraceptives had an increased risk for all stroke (fatal and nonfatal) (odds ratio [OR] adjusted for social class and smoking 1.5, 95% CI 1.1 to 2.0) and fatal stroke (adjusted OR 2.3, CI 1.2 to 4.4). The risk estimate for all stroke among current users of oral contraceptives was twice that of former users (adjusted OR 2.5, CI 1.5 to 4.0 vs 1.3, CI 0.9 to 1.8, respectively), whereas former users were at increased risk for fatal stroke compared with current users (adjusted OR 2.4, CI 1.2 to 4.7 vs 1.8, CI 0.6 to 5.3, respectively). The risk in former users was restricted to smokers. Estrogen dose per pill was directly related to the risk for stroke.

Conclusions

Oral contraceptive use was associated with an increased risk for stroke. The association remained after adjustments were made for smoking and social class.

Sources of funding: Royal College of General Practitioners; Schering AG (Germany); Schering Healthcare Limited (United Kingdom); Wyeth-Ayerst (United States); British Heart Foundation; Medical Research Council.

For article reprint: Dr. P. Hannaford, Royal College of General Practitioners, Centre for Primary Care Research and Epidemiology, Department of General Practice and Primary Care, Foresterhill Health Centre, Aberdeen AB25 2A4, Scotland, United Kingdom. FAX 44-1224-840613.


Commentary

S ee alsoOral contraceptive use was not associated with mortality

Oral contraceptives, known to millions simply as "the pill," are one of the most frequently prescribed medications. Despite the many data on the safety and efficacy of the pill, some concerns remain about the long-term safety of oral contraceptives; the Harvard Nurses' Health Study looked broadly at mortality as the end point, and the Royal College of General Practitioners' Study looked more narrowly at stroke as the end point.

The Harvard Nurses' Health Study is an important contribution to the literature on oral contraceptive safety because of the large cohort of women followed and the 12-year duration of the study. Based on analysis of over 2800 deaths, the study concludes that the use of the pill does not increase the risk for overall mortality. Women who use the pill were not at increased risk for total cancer mortality, even though an increased risk for breast cancer mortality existed (caused, in part, by the inverse relation of ovarian and endometrial cancer with oral contraceptive use).

The increased risk for breast cancer (primarily in current users) persisted even when adjustments were made for the usual risk factors. Length of lactation, however, was not reported to be assessed as a risk. Evidence that an adequate length of lactation reduces the risk for premenopausal breast cancer is emerging (1). The results of a study in the United Kingdom suggest that the increased risk for breast cancer in women using the pill may be related to the dose of estrogen (2).

The major limitation to applying the results of this study to current practice is that the cohort of women assembled for the study in 1976 used the oral contraceptives on the market at the time. Therefore, the mortality associations largely reflect the use of pills at a much higher dose. It is only speculation, but the mortality predictions based on the newer low-dose oral contraceptives may actually be favorable because of neutral effects on breast cancer risk and improvement of cardiovascular risk.

Since the 1970s, a significant decline in the incidence of stroke and cardiovascular mortality has occurred (3). The study by Hannaford and colleagues found that social class, smoking status, and hypertension were important risk factors for stroke in women. Unfortunately, other recognized risk factors for stroke, such as hyperlipidemia, atrial fibrillation, alcohol use, and diabetes mellitus, were not controlled for in this case-control analysis. Persons who were nonsmoking former users of the pill did not have an elevated risk for stroke. Most women who had strokes while using oral contraceptives were using the older, higher-dose pills.

Women who are over 35 years of age and smoke should not use oral contraceptives. Otherwise, women should be reassured about the overall safety of the pill and should also be counseled on the potential noncontraceptive benefits of the pill, such as the decrease in the incidence of ovarian cancer.

Holly L. Thacker, MD
Cleveland Clinic FoundationCleveland, Ohio, USA


References

1. Newcome PA, Storer BE, Longnecker MP, et al. Lactation and a reduced risk of premenopausal breast cancer. N Engl J Med. 1994;330:81-7.

2. U.K. National Case-Control Study Group. Oral contraceptive use and breast cancer risk in young women: subgroup analyses. Lancet. 1990;335:1507-9.

3. Garraway WM, Whisnant JP, Furlan AJ, et al. The declining incidence of stroke. N Engl J Med. 1979;300:449-52.