Heart attack. Ischemic heart disease results from an impediment to circulation that deprives the heart of adequate blood supply. Myocardial infarction—heart attack—is the resulting death of heart muscle cells. Ischemic heart disease can develop gradually from atherosclerosis, in which deposits on the walls of coronary arteries restrict blood flow to the heart muscle, or it can result from a thrombus, or clot, that suddenly blocks a coronary artery. Myocardial infarction is rare in young women who do not smoke or have other clinical risk factors (122, 463, 540).

Using OCs may somewhat increase heart attack risk, but risk is largely limited to older women who smoke or have high blood pressure. Early case-control studies found that the risk of myocardial infarction (heart attack) in current OC users was two to four times greater than in nonusers (286, 287, 288, 290, 431). Recent studies suggest risk less than twice that of nonusers. For example, a recent US case-control study found that OC use increased risk by about 1.7 times. In this study an estimated 5% of myocardial infarction cases were attributable to current OC use, the equivalent of less than three additional heart attacks per 1 million US women in one year of OC use (425). Two other recent case-control studies, one in the US (389) and one in the UK (465), found no significantly increased risk among either current or past OC users. The findings of lower risk may be attributable to use of lower-dose OCs and perhaps also to better screening of potential pill users for risk factors such as smoking (463).

Combining OC use with other risk factors for heart disease, particularly smoking, hypertension, and long-term or uncontrolled diabetes, raises the risk of myocardial infarction substantially (288, 353, 463). Relative risk* increases considerably in pill users who smoke (95, 163, 353, 388, 415, 463). Between 1989 and 1993 the World Health Organization (WHO) conducted a large case-control study of cardiovascular disease and hormonal contraceptives in 21 hospitals in Europe and in developing countries of Africa, Asia, and Latin America. OC users with histories of hypertension or who were heavy smokers were at a much greater risk of heart attack relative to OC users without either of these risk factors (see Table 3).

*Relative risk is a measure of how much a particular factor influences the risk of a specified outcome. For example, a relative risk of 2 associated with a factor means that people with the factor face twice the risk of having a specified outcome that people without the factor have. A relative risk of 0.5 means that people with the factor face half the risk of the specified outcome that people without the factor have (a protective effect).

The WHO study found the relative risk of heart attack associated with OC use was higher among women who had not had their blood pressure checked before starting to use OCs—presumably because some of them did have high blood pres-sure, whereas the group of OC users who had been screened excluded most women with high blood pressure (539).

Among nonsmoking OC users who had their blood pressure checked before starting OCs and had no other risk factors for heart attack, there was no appreciable increase in risk in either European or developing countries (539, 540). The researchers conclude that:

Women who do not smoke, who have their blood pressure checked, and who do not have hypertension or diabetes are at no increased risk of myocardial infarction if they use combined oral contraceptives, regardless of age. There is no increase in the risk of myocardial infarction with increasing duration of use of combined oral contraceptives. There is no increase in the relative risk of myocardial infarction in past users of oral contraceptives. These conclusions appear to apply equally to women in developed and developing countries. (540)

Recent studies have suggested no increased risk of myocardial infarction among users of third-generation OCs with no other risk factors (222, 268, 270). The rarity of myocardial infarction in women of reproductive age, the large number of different OC formulations, and the differing geographic distributions of users of specific formulations will make it difficult to compare various formulations in detail, however (353).

Recent studies—and most older ones—have found that heart attack risk does not increase with duration of OC use. Also, risk does not persist after a woman stops using OCs (3, 10, 95, 104, 288, 289, 375, 415, 425, 431, 442, 443, 465, 539).

Planned Parenthood Federation of America

Smoking increases the risk of heart attack and stroke especially for older women who use oral contraceptives. This US poster warns of the risk and urges pill users not to smoke.

Studies with low-dose OCs in the 1980s and 1990s suggest less overall risk of stroke than did earlier studies (464). The first studies of the health risks of OC use, conducted in the 1960s and 1970s, suggested about a fivefold greater risk of any type of stroke among OC users than among nonusers (81, 213, 224, 263, 264, 355, 375, 441, 490). Now, based on the results of a multi-center WHO study (367) and other recent studies (192, 354, 412), the estimated risk of ischemic stroke among OC users is about 2.5 times greater than the risk among nonusers (131). The more recent studies provide more information on ischemic stroke than on hemorrhagic stroke.

Lower doses appear to have reduced the risk. For example, in the Oxford/FPA cohort study, the relative risk of stroke for OC users appeared to drop as the study progressed. In 1984 the study reported relative risks of 1.5 to 2.0 for subarachnoid hemorrhage and 2.3 to 3.2 for other types of stroke among OC users compared with nonusers (497), down from 5.0 for all types in 1976 (490).

The multicenter WHO study—the largest case-control study of stroke and OCs by far—found an overall relative risk of ischemic stroke of about 3 among OC users. As with heart attacks, other risk factors make a big difference to the risk of OC use (see Table 4). Current OC users who did not smoke, had their blood pressure checked, and did not have high blood pressure were at 1.5 times greater risk than nonusers. In contrast, OC users who smoked faced a higher risk—about two times greater than among nonsmoking OC users in the developing countries studied and about 3.5 times greater in Europe. Current OC users with a history of hypertension faced the greatest risk—about five and four times greater than for other OC users. As in the WHO study of heart attack, the risk of ischemic stroke was lower among women who reported having their blood pressure checked before starting OCs than among those who did not (367).

The WHO study produced conflicting findings on the relationship between dosage and ischemic stroke risk. In Europe lower doses meant lower risks, while in the developing countries the pattern was reversed. The researchers suggest that the opposing patterns reflect different levels of other risk factors for ischemic stroke. In both Europe and the developing countries, however, risk did not rise significantly with continuing OC use, and elevated risk did not appear to persist after women stopped using OCs (367).

Migraine headaches have been linked to a twofold or greater increased risk of ischemic stroke. Several studies have found that OC users with a history of migraine are two to four times more likely to have an ischemic stroke than women with a history of migraine who do not use OCs (69, 272, 273, 274, 411, 475). For example, a case-control study conducted in European hospitals from the WHO study of cardiovascular disease and hormonal contraceptives found that, compared with women not using OCs and having no history of migraine, ischemic stroke was 6.6 times more likely among OC users with a history of migraine, and 2.3 times more likely among nonusers with a history of migraine (69). Studies suggest risk is greater among women who have severe migraine headaches with "aura"—focal neurologic symptoms such as blurred vision, temporary loss of vision, seeing flashing lights or zigzag lines, or trouble speaking or moving (61, 69, 411, 475). The recent studies (61, 69, 273, 475) led a March 2000 meeting of experts convened by WHO to recommend that a woman who has migraine headaches with focal neurologic symptoms should not start combined OCs. The group recommended that a woman age 35 or older should choose another method if possible if she has migraine headaches even without focal neurologic symptoms. Mild or severe headaches that are not migrainous do not rule out OC use (557).

For hemorrhagic stroke, the WHO study found a slightly increased risk among OC users in general (see Table 5). The difference was statistically significant in developing countries but not in the European countries. In both developing and European countries, current OC users age 35 or over had a significantly increased risk of hemorrhagic stroke, with relative risks of 2.5 and 2.2, respectively, compared with nonusers of OCs. The relative risk among current OC users who smoked was three to four times that of nonusers who did not smoke. Also, current users with a history of hypertension faced a substantially higher relative risk than nonusers with no such history. As with ischemic stroke, the duration of OC use did not affect the risk of hemorrhagic stroke, and the elevated risk did not persist after OC use ended. Risk did not vary with estrogen dose or with progestin dose or type (537, 540).

Because, in combination, hypertension and OC use increased the risk of stroke and myocardial infarction far more than would either risk factor alone, WHO medical eligibility criteria for OC use were recently revised to recommend that women who know that they have high blood pressure—systolic pressure of 140 mm Hg or higher and/or diastolic pressure of 90 or higher—or, where blood pressure cannot be evaluated, who have a history of hypertension should choose another contraceptive method (557). (Blood pressure must be properly taken, and one reading is not enough to diagnose high blood pressure.)

In areas where medical services are limited, blood pressure checks for OC users may be impractical. In these service areas, maternal mortality and morbidity tend to be greater risks than any risks associated with OC use (540).

In any case, the benefit of screening potential combined OC users for high blood pressure and withholding OCs from women with high blood pressure would not be substantial if hypertension itself cannot be treated. A recent analysis conducted for WHO pointed out that this screening would prevent only about 10% of stroke and heart attack cases attributable to OC use. In particular, screening women under age 35 for high blood pressure would not prevent an appreciable number of cardiovascular disease cases or deaths attributable to OC use. At the same time, "false positive" diagnoses of hypertension would needlessly prevent some women from using OCs (556).

From a public health perspective, the impact of cardiovascular disease attributable to OC use is slight, particularly since most OC users are young and do not have other risk factors for cardiovascular disease. The analysis for WHO points out that the additional number of cardiovascular disease cases and deaths among OC users depends greatly on age. For example, among one million OC users under age 35, 20% of whom smoke, fewer than 20 deaths annually would be due to OC use. By comparison, among one million OC users over age 35, 20% of whom smoke, 24 to 96 deaths annually would be attributable to OC use, depending on the region (556).

Thromboembolism. Thromboembolism is an obstruction of a blood vessel by a blood clot. The most common thrombo-embolic disorder in OC usersÅknown as venous thrombo- embolism (VTE), or deep vein thrombosisÅinvolves clots that form in veins deep in the leg. These clots sometimes circulate to the lungs, where they become potentially fatal pulmonary embolisms. A multinational study by WHO, conducted from 1989 to 1993 (366), and three smaller studies in the mid-1990s (34, 221, 440) found that modern low-dose OCs pose less risk of thromboembolism than indicated by earlier studies that involved mostly first-generation pills.

The new case-control studies reported a risk of VTE about three times greater among users of second-generation OCs than among women not using OCs and about six times greater among users of third-generation OCs containing desogestrel and gestodene (131). There is debate about whether the difference in risk between second- and third-generation pills is real or due to bias in the studies (88, 131, 132, 194, 223, 267, 269, 275, 368, 440, 447, 503, 540, 554).

When the findings were released in 1995, they caused a "pill scare" in the news media of the UK and other European countries where third-generation OCs are most widely used. Responding to the publicity, many women switched to other OCs or stopped taking pills altogether. In the months following, the number of unintended pregnancies and abortions increased substantially (15, 75, 76, 118, 218, 257, 376, 528).

The estimated risk of VTE is low with all modern low-dose OCs —including those containing desogestrel and gestodene—and all low-dose OCs pose less risk of VTE than previous higher-dose formulations. For users of high-dose OCs, early studies suggested that about 80 cases of VTE per 100,000 women per year could be attributed to OC use (197, 221, 358, 441). By comparison, recent studies estimate that the annual number of VTE cases attributable to second-generation OCs ranges from about 6.5 cases per 100,000 women per year at ages 20 to 24 to 12 cases per 100,000 per year at ages 40 to 44. The number attributable to third-generation OCs ranges from about 16 cases per 100,000 at ages 20 to 24 to 30 cases per 100,000 at ages 40 to 44 (131). VTE risk associated with pregnancy is about 60 cases per 100,000 pregnancies (86).

The risk of death from VTE is slight. Worldwide, among women not using OCs, an estimated 0.6 to 1.2 deaths per million women per year can be attributed to VTE. Based on recent case-control studies, an estimated 1.3 to 2.4 additional deaths per million women per year occur among OC users (131).

Increased blood pressure and hypertension. Many studies have found small but statistically significant increases in blood pressure in women taking combined OCs with 50 mg of estrogen or more (42, 137, 138, 300, 435, 510, 511, 525). Increases averaged about 6 mm Hg for systolic blood pressure and 2 mm Hg for diastolic blood pressure (417). Studies have reported generally comparable increases in blood pressure among users of low-dose combined OCs as well (162, 241, 320, 327, 525, 534).

In some women these increases are enough to lead to a diagnosis of hypertension (blood pressure of 140/90 or higher). Usually, however, blood pressure remains within normal ranges and declines once the woman stops using OCs (55, 71, 137, 241, 510). For example, a recent US cohort study of about 68,000 nurses ages 25 to 42 found that, after adjusting for other possible risk factors, OC users were almost twice as likely to develop hypertension as women who had never used OCs. Risk increased with duration of use but decreased rapidly after women stopped using OCs (71).