Ischaemic stroke and combined oral contraceptives: results of an international, multicentre, case-control study. WHO Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception.

BACKGROUND: The association between use of oral contraceptives (OCs) and cerebral infarction was established in studies from northern Europe and the USA during the 1960s and 1970s. Since then, the constituents of hormonal OCs have changed and now contain lower doses of oestrogen and progestagen. Current recommendations restrict OC use to younger women who do not have other risk factors for cardiovascular disease. In this international study we assessed the risk of OC-associated first stroke in women from Europe and other countries throughout the world.
METHODS: In this hospital-based, case-control study, we assessed the risk of ischaemic stroke in association with current use of combined OCs in 697 cases, aged 20-44 years, and 1962 age-matched hospital controls in 21 centres in Africa, Asia, Europe, and Latin America. The diagnosis of ischaemic stroke was almost exclusively based on computed tomography (CT), magnetic resonance imaging (MRI), or cerebral angiography carried out within 3 weeks of the clinical event. All cases and controls were interviewed while in hospital with the same questionnaire, which included information on medical and personal history, details of lifetime contraceptive use, and blood-pressure measurements before the most recent episode of OC use.
FINDINGS: The overall odds ratio of ischaemic stroke was 2.99 (95% CI 1.65-5.40) in Europe and 2.93 (2.15-4.00) in the non-European (developing) countries. Odds ratios were lower in younger women and those who did not smoke, and less than 2 in women who did not have hypertension and who reported that their blood pressure had been checked before the current episode of OC use. By contrast, among current OC users with a history of hypertension, the odds ratio was 10.7 (2.04-56.6) in Europe and 14.5 (5.36-39.0) in the developing countries. In Europe, the odds ratio associated with current use of low-dose OCs (< 50 micrograms oestrogen) was 1.53 (0.71-3.31), whereas for higher-dose preparations it was 5.30 (2.56-11.0). In the developing countries, there was no significant difference between overall estimates of risk associated with use of low-dose or higher-dose OCs (3.26 [2.19-4.86] vs 2.71 [1.75-4.19]). This differential effect of dose in Europe and the developing countries is likely to be due to different levels of other risk factors among users of low-dose and higher-dose OCs in the two groups of countries. There was no significant increase in odds ratios with increasing duration of OC use among current users; odds ratios were not significantly increased after cessation of OC use.
INTERPRETATION: The incidence of ischaemic stroke is low in women of reproductive age and any risk attributable to OC use is small. The risk can be further reduced if users are younger than 35 years, do not smoke, do not have a history of hypertension, and have blood pressure measured before the start of OC use. In such women OC preparations with low oestrogen doses may be associated with even lower risk.