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Volume 345:1787-1793 December 20, 2001 Number 25 Next

Abstract PDF Editorial by Chasan-Taber, L. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background An association between the use of oral contraceptives and the risk of myocardial infarction has been found in some, but not all, studies. We investigated this association, according to the type of progestagen included in third-generation (i.e., desogestrel or gestodene) and second-generation (i.e., levonorgestrel) oral contraceptives, the dose of estrogen, and the presence or absence of prothrombotic mutations.

Methods In a nationwide, population-based, case–control study, we identified and enrolled 248 women 18 through 49 years of age who had had a first myocardial infarction between 1990 and 1995 and 925 control women who had not had a myocardial infarction and who were matched for age, calendar year of the index event, and area of residence. Subjects supplied information on oral-contraceptive use and major cardiovascular risk factors. An analysis for factor V Leiden and the G20210A mutation in the prothrombin gene was conducted in 217 patients and 763 controls.

Results The odds ratio for myocardial infarction among women who used any type of combined oral contraceptive, as compared with nonusers, was 2.0 (95 percent confidence interval, 1.5 to 2.8). The adjusted odds ratio was 2.5 (95 percent confidence interval, 1.5 to 4.1) among women who used second-generation oral contraceptives and 1.3 (95 percent confidence interval, 0.7 to 2.5) among those who used third-generation oral contraceptives. Among women who used oral contraceptives, the odds ratio was 2.1 (95 percent confidence interval, 1.5 to 3.0) for those without a prothrombotic mutation and 1.9 (95 percent confidence interval, 0.6 to 5.5) for those with a mutation.

Conclusions The risk of myocardial infarction was increased among women who used second-generation oral contraceptives. The results with respect to the use of third-generation oral contraceptives were inconclusive but suggested that the risk was lower than the risk associated with second-generation oral contraceptives. The risk of myocardial infarction was similar among women who used oral contraceptives whether or not they had a prothrombotic mutation.

Methods

Study Design

The Risk of Arterial Thrombosis in Relation to Oral Contraceptives (RATIO) study is a population-based case–control study of the relation of arterial disease to the use of oral contraceptives among women 18 to 49 years of age in the Netherlands. The study protocol was approved by the ethics committees of the participating hospitals (see the Appendix). Oral informed consent was obtained from all participants.

Identification of Women with Myocardial Infarction

Eligible patients were women 18 to 49 years of age who were hospitalized for a first myocardial infarction between January 1990 and October 1995. Myocardial infarction was defined by the presence of symptoms, elevated cardiac-enzyme levels, and electrocardiographic changes.²⁵ The patients were identified through a search of computerized hospital data bases for International Classification of Diseases, 9th Revision, Clinical Modification codes for acute myocardial infarction. Of the 321 women who were admitted to the 16 participating centers during this period, 29 (9 percent) were excluded: 19 died during admission, 9 died between discharge and the start of the study, and 1 was unable to participate. The medical records of all patients were reviewed by one investigator. Of the 292 remaining patients, 21 could not be located and 23 declined to participate (response rate, 85 percent).

Control Women

The study was designed to investigate three types of arterial disease: myocardial infarction, ischemic stroke, and peripheral arterial disease; the results for each type are reported separately. We identified and recruited one large control group through random-digit dialing.²⁶ In this method, private telephone numbers randomly generated by a computer are dialed until someone answers or at least seven attempts have been made at various times of the day and the week, including the weekend. We reached someone at 98 percent of the numbers after a total of 15,725 telephone calls. Once it was ascertained that a household included a woman who was eligible for the study, she was asked to participate. We recruited control women from the six geographic areas where the patients lived, and using questionnaires, we assigned each an index year corresponding to the one of the six years (1990 to 1995) in which the patients had had an index event. Therefore, a control woman randomly received one of six questionnaires concerning one of the index years. All questions elicited information about either the index date (in the case of questions about the body-mass index, menopausal status, level of education, and family history), the year before the index date (in the case of questions about a history of hypertension, diabetes, hypercholesterolemia, alcohol use, and smoking), or the month before the index date (in the case of questions about the use of oral contraceptives). The index date was the date of the myocardial infarction in the patients and midyear in the controls. To minimize age differences between the patients and the controls, control women in the older age groups were oversampled by increasing the age limit of eligibility criteria during recruitment. The control group therefore was a population sample stratified according to age (in five-year categories), area of residence, and calendar year.

Eligible controls were women 18 to 49 years of age who had no history of coronary, cerebral, or peripheral arterial disease. A total of 1259 eligible women were reached by random-digit dialing, 925 of whom agreed to participate and returned the questionnaire (73 percent).

Data Collection

The standardized questionnaire that was mailed to patients and controls included questions about demographics, use of oral contraceptives, reproductive history, height and weight, and the presence or absence of a history of hypertension, diabetes, hypercholesterolemia, and cigarette smoking and a family history of cardiovascular disease. Color photographs of all oral-contraceptive pills marketed in the Netherlands during the study period were included to help women recall the formulations they might have used. Oral contraceptives were divided into four groups according to the type of progestagens included: first-generation formulations containing lynestrenol or norethindrone, second-generation formulations containing levonorgestrel, third-generation formulations containing desogestrel or gestodene, and oral contraceptives containing an estrogen and other progestagens (cyproterone or norgestimate) or a progestagen alone. We also classified oral contraceptives according to the dose of estrogen. Women were categorized according to their use of oral contraceptives (never, former, or current). The level of education was categorized as primary school or less, secondary school, or higher education or university. Obesity was defined as a body-mass index (the weight in kilograms divided by the square of the height in meters) of at least 27.3.²³ Women were classified as having hypertension, diabetes, or hypercholesterolemia when they reported that the condition had been diagnosed by a physician or that they had been taking medication for the condition before the index date. Smoking status was categorized as never, former, or current. Current smokers were those who reported smoking in the year before the index date. Alcohol use was categorized as none, 1 to 15 drinks per week, and more than 15 drinks per week. A family history of cardiovascular disease was defined as the occurrence of myocardial infarction, stroke, or peripheral arterial disease before the age of 60 years in one or more first-degree relatives.

Samples of venous blood or buccal swabs were obtained from 217 patients (88 percent) and 763 controls (82 percent) who consented to undergo DNA analysis for factor V Leiden and the G20210A mutation in the prothrombin gene. The polymerase chain reaction was used for the analysis.^27,28

Statistical Analysis

We used unconditional logistic-regression analyses to calculate odds ratios for the relation between the use of oral contraceptives and myocardial infarction, and we derived confidence intervals from the model. We adjusted for the three stratification factors — age (in five-year categories), area of residence, and calendar year — and for putative confounding factors (smoking status; presence or absence of hypercholesterolemia, diabetes, hypertension, obesity, and a family history of cardiovascular disease; level of education; and alcohol intake). To exclude an effect of the dose of estrogen in the analyses that were focused on the type of progestagen included in the oral contraceptive, we excluded women who used formulations other than those containing 30 µg of ethinyl estradiol: 28 women (13 patients and 15 controls) used second-generation oral contraceptives containing 50 µg of ethinyl estradiol, 67 women (13 patients and 54 controls) used triphasic second-generation oral contraceptives, 3 women (all controls) used triphasic third-generation oral contraceptives, 18 women (2 patients and 16 controls) used third-generation oral contraceptives containing 20 µg of ethinyl estradiol, and in 6 women (1 patient and 5 controls) the dose of ethinyl estradiol was unknown. In a further effort to minimize the possibility of confounding, in particular by the presence of preexisting disease, we repeated the analysis after excluding women with major cardiovascular risk factors. We also directly investigated whether confounding was present, in particular prescription bias, by analyzing risk factors and oral-contraceptive use in the control women. Analyses of the dose of ethinyl estradiol were restricted to women who used oral contraceptives containing 50 µg of ethinyl estradiol and 150 µg of levonorgestrel or 30 µg of ethinyl estradiol and 125 µg of levonorgestrel. Finally, we assessed the effect of combinations of risk factors: the use of oral contraceptives and conventional risk factors (current smoking, hypercholesterolemia, diabetes, and hypertension), as well as factor V Leiden and the G20210A mutation in the prothrombin gene.

Results

Table 1 shows the characteristics of the 248 women who had had a myocardial infarction and the 925 control women. Patients ranged in age from 24 to 49 years (mean, 43), and controls ranged in age from 18 to 49 years (mean, 38). Patients had a higher prevalence than controls of major risk factors for cardiovascular disease, such as hypertension (24 percent vs. 6 percent), hypercholesterolemia (11 percent vs. 3 percent), diabetes (6 percent vs. 1 percent), and current smoking (84 percent vs. 43 percent). Patients also had a lower level of education than controls (11 percent vs. 27 percent with post–secondary-school education).

View this table: [in this window] [in a new window]   Table 1. Characteristics of 248 Women with a First Myocardial Infarction and 925 Control Women.

 
The risk of myocardial infarction among users of any type of oral contraceptive was twice that of nonusers (95 percent confidence interval, 1.5 to 2.8), after adjustment for age, calendar year, and area of residence (Table 2). Additional adjustment for putative confounding factors increased the odds ratio in most age categories, and the overall risk remained doubled (Table 2). Women with no conventional risk factors (hypertension, hypercholesterolemia, diabetes, or smoking) who used oral contraceptives had a relative risk of myocardial infarction of 3.1 (95 percent confidence interval, 1.0 to 9.2). The duration of oral-contraceptive use did not differ significantly between patients and controls (median, 10 years).

View this table: [in this window] [in a new window]   Table 2. Odds Ratios for Myocardial Infarction among Women Who Used Any Type of Oral Contraceptive, According to Age.

 
Second-generation oral contraceptives containing levonorgestrel were used by 24 percent of the patients and 19 percent of the controls (Table 3). Third-generation oral contraceptives containing desogestrel or gestodene were used by 8 percent of the patients and 12 percent of the controls. The odds ratio for myocardial infarction was 2.8 (95 percent confidence interval, 1.3 to 6.3) for women who used first-generation contraceptives, as compared with those who had not used oral contraceptives; 2.4 (95 percent confidence interval, 1.6 to 3.6) for women who had used second-generation contraceptives; and 1.3 (95 percent confidence interval, 0.8 to 2.3) for women who had used third-generation contraceptives (Table 3). When we restricted this analysis to users of second-generation oral contraceptives (37 patients and 94 controls) and third-generation oral contraceptives (18 patients and 91 controls) that contained 30 µg of ethinyl estradiol, the odds ratios did not change substantially: 2.7 for users of second-generation oral contraceptives (95 percent confidence interval, 1.6 to 4.3) and 1.6 for users of third-generation oral contraceptives (95 percent confidence interval, 0.9 to 2.9). A direct comparison of oral contraceptives containing 30 µg of ethinyl estradiol and levonorgestrel, desogestrel, or gestodene revealed an odds ratio for myocardial infarction of 0.5 (95 percent confidence interval, 0.2 to 1.1) for third-generation as compared with second-generation oral contraceptives (after adjustment for stratification variables). The odds ratios were similar for third-generation brands containing desogestrel or gestodene. Further adjustment for confounding did not affect these estimates (Table 3).

View this table: [in this window] [in a new window]   Table 3. Odds Ratios for Myocardial Infarction in Relation to the Type of Progestagen Included in the Oral Contraceptive.

 
In an analysis that was restricted to the 41 patients and 104 controls who had used contraceptives with a second-generation progestagen, as compared with those who had not used oral contraceptives, the risk of myocardial infarction was similar for oral contraceptives with different doses of estrogen. The odds ratio was 2.0 (95 percent confidence interval, 0.6 to 7.3) for brands containing 50 µg of ethinyl estradiol with levonorgestrel and 2.6 (95 percent confidence interval, 1.6 to 4.2) for brands containing 30 µg of ethinyl estradiol with levonorgestrel. A direct comparison of oral contraceptives containing levonorgestrel and ethinyl estradiol revealed an odds ratio of 1.7 (95 percent confidence interval, 0.4 to 7.9) for all brands that contained less than 50 µg of ethinyl estradiol as compared with brands that contained 50 µg of ethinyl estradiol or more.

We analyzed the effect of other cardiovascular risk factors in women who used oral contraceptives, as compared with the reference category of women who had not used oral contraceptives and who did not have the given risk factor (Table 4). The adjusted odds ratios for myocardial infarction among women who had not used oral contraceptives were 7.9 (95 percent confidence interval, 4.9 to 12.9) for those who smoked, 5.1 (95 percent confidence interval, 2.9 to 8.8) for those with hypertension, 3.3 (95 percent confidence interval, 1.6 to 6.8) for those with hypercholesterolemia, 4.2 (95 percent confidence interval, 1.6 to 10.9) for those with diabetes, and 3.4 (95 percent confidence interval, 2.2 to 5.3) for those who were obese. Among women who had used oral contraceptives, the risk of myocardial infarction was highest among those who smoked (odds ratio, 13.6), those who had diabetes (odds ratio, 17.4), and those who had hypercholesterolemia (odds ratio, 24.7).

View this table: [in this window] [in a new window]   Table 4. Odds Ratios for Myocardial Infarction in Relation to the Use of Oral Contraceptives and to the Presence or Absence of Cardiovascular Risk Factors.

 
Factor V Leiden or a G20210A mutation in the prothrombin gene was present in 18 of 214 patients (8 percent) and 58 of 760 controls (8 percent). Two control women carried both mutations. The odds ratio for myocardial infarction among women with a prothrombotic mutation was 1.1 (95 percent confidence interval, 0.6 to 1.9), as compared with women without a mutation. In the subgroup of smokers the presence of one of these mutations increased the risk of myocardial infarction by 1.6 (95 percent confidence interval, 0.8 to 3.3). Among women younger than 35 years of age who had a prothrombotic mutation, the odds ratio was 1.6 (95 percent confidence interval, 0.4 to 5.8), and among those who were at least 35 years old it was 0.9 (95 percent confidence interval, 0.5 to 1.7). The use of oral contraceptives doubled the risk of myocardial infarction among women without a prothrombotic mutation (odds ratio, 2.1; 95 percent confidence interval, 1.5 to 3.0) and among women with a prothrombotic mutation (odds ratio, 1.9; 95 percent confidence interval, 0.6 to 5.5).

Discussion

In this case–control study we found that the use of currently available combined oral contraceptives increased the overall risk of a first myocardial infarction. As compared with nonusers, women who used first- and second-generation oral contraceptives had a significantly increased risk, but the results were inconclusive for women who used third-generation oral contraceptives. The risk was increased in all age groups except for the small group of women who were 18 to 24 years old, and there were no significant differences in the odds ratios between the age categories or between the doses of estrogen. The risks were highest among users of oral contraceptives who smoked, who had diabetes mellitus, or who had hypercholesterolemia, but they were not affected by the presence of factor V Leiden or the G20210A mutation in the prothrombin gene.

The use of second-generation oral contraceptives increased the risk of myocardial infarction by a factor of 2.5. The use of third-generation oral contraceptives did not increase the risk significantly (odds ratio, 1.3). The direct comparison of second- and third-generation oral contraceptives suggested that the use of third-generation agents was associated with a lower risk of myocardial infarction, but the confidence interval was wide and therefore a definite conclusion could not be reached.

Five studies, including ours, have directly compared the effect of the use of second- and third-generation oral contraceptives on the risk of myocardial infarction,^{17,18,19,20,21} with reported odds ratios that ranged from 0.3¹⁸ to 1.8.²¹ Only the study by Dunn et al.²¹ and our study were designed to assess whether the use of third-generation oral contraceptives has a different effect on the risk of myocardial infarction than does the use of second-generation agents and included a sufficient number of women who used third-generation oral contraceptives to allow conclusions to be drawn. Dunn et al. suggested that the risk is higher with third-generation than with second-generation oral contraceptives (odds ratio, 1.8; 95 percent confidence interval, 0.7 to 4.8), whereas we found the reverse (odds ratio, 0.5; 95 percent confidence interval, 0.2 to 1.1). As can be seen from the confidence interval, the study by Dunn et al. also did not permit a definite conclusion to be reached.

Our study was designed as a nationwide, population-based, case–control study, with patients recruited from all eight academic centers in the Netherlands and eight surrounding hospitals. One of the strengths of our study is that the use of both second- and third-generation oral contraceptives is widespread in the Netherlands, thus providing a large population of potential study subjects. In the evaluation of our results, we also need to address the possibility of bias. Because all patients with known myocardial infarction were hospitalized and the patients were selected entirely on the basis of the discharge diagnosis, selection bias is improbable. The rate of nonresponse was fairly low and was unlikely to have been associated with the use of oral contraceptives or the type of agent used. Information bias was unlikely, because the women were not told about the primary objective of the study and the questionnaire elicited information about many issues. The subjects' recall was optimized by the inclusion in the questionnaire of color photographs of all available oral contraceptives.²⁹ However, the possibility of recall bias cannot be excluded. Patients who died after a myocardial infarction were not included in the study, but it is unlikely that the use of oral contraceptives would be a specific contributing factor to the case fatality rate.

Selective prescription following screening for risk factors may affect the risks associated with the use of oral contraceptives. We therefore investigated risk-factor status according to the use of oral contraceptives in the control women and found little difference in the prevalence of cardiovascular risk factors between those who used oral contraceptives and those who did not (Table 5). There were small differences in the incidence of hypercholesterolemia and diabetes and in body-mass index, which were in part explained by the younger age of oral-contraceptive users. To minimize the likelihood of confounding, we also conducted an analysis restricted to women with no cardiovascular risk factors and still found that women who used oral contraceptives had a risk of myocardial infarction that was three times the risk among nonusers.

View this table: [in this window] [in a new window]   Table 5. Prevalence of Risk Factors for Cardiovascular Events in Control Women, According to Their Use of Oral Contraceptives.

 
Although the risk of myocardial infarction in users of oral contraceptives is small in absolute terms, it has an important effect on women's health, since 35 to 45 percent of women of reproductive age use oral contraceptives.³⁰ Because all combined oral contraceptives are equally effective means of birth control, the issue of safety is paramount. Since the absolute risk of myocardial infarction is highly age-dependent, the risk associated with the use of oral contraceptives will have the greatest effect in older women. A large number of women who were 35 years of age or older still used oral contraceptives (26 percent). This finding, however, may be specific to the Netherlands (the rate is 24 percent in national statistics).³⁰ Before prescribing oral contraceptives, clinicians should screen women for conventional risk factors for cardiovascular events, and they should remember that the most important advice they can give these women remains to quit smoking.

Supported by a grant (97-063) from the Netherlands Heart Foundation. Dr. Helmerhorst has supervised research studies sponsored by multiple pharmaceutical companies that manufacture oral-contraceptive agents.

We are indebted to Dr. Bruno Stricker for advice during the planning of the study, to Dr. Jan Vandenbroucke and Dr. Tim Farley for critical reading of and advice on the analysis and writing, to Annemieke van Dam for her work in contacting patients and controls as well as for general data management, to Esther van Lunteren and Marjon de Boer for their assistance in recruiting controls, to Tineke Krommenhoek-van Es for the DNA analyses, to Dr. Hans Vos for supervision, and to all the women who participated in this project.

Source Information

From the Thrombosis and Hemostasis Research Center, Department of Hematology (B.C.T., F.R.R.), and the Departments of Cardiology (V.M.C.), Obstetrics, Gynecology, and Reproductive Medicine (F.M.H.), and Clinical Epidemiology (F.R.R.), Leiden University Medical Center, Leiden; and the Julius Center for General Practice and Patient-Oriented Research (M.A.A.J.B., J.M.K., A.A., Y.G.) and the Department of Neurology (A.A.), University Medical Center, Utrecht — both in the Netherlands.

Address reprint requests to Dr. Rosendaal at the Department of Clinical Epidemiology, Leiden University Medical Center, Bldg. 1, C9-P, P.O. Box 9600, 2300 RC Leiden, the Netherlands, or at f.r.rosendaal{at}lumc.nl.

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The following investigators and centers in the Netherlands participated in the study: Leiden University Medical Center, Leiden — E.E. van der Wall; Sint Antonius Hospital, Nieuwegein — N.M. van Hemel; Academic Medical Center, Amsterdam — R.J.G. Peters; Rijnstate Hospital, Arnhem — H.A. Bosker; Medical Center Haaglanden, Westeinde Hospital, The Hague — J. Kolf; University Medical Center, Nijmegen–St. Radboud — F.W.A. Verheugt; Leyenburg Hospital, The Hague — B.J.M. Delemarre; University Medical Center, Rotterdam–Dijkzigt — F.A.M. Jonkman; Academic Hospital, Maastricht — F. Vermeer; Rijnland Hospital, Leiderdorp — C. van Rees; Medical Center Free University, Amsterdam — O. Kamp; University Medical Center, Utrecht — E.O. Robles de Medina (deceased); Academic Hospital, Groningen — M. van den Berg; Bronovo Hospital, The Hague — P.R.M. van Dijkman; Sint Franciscus Hospital, Rotterdam — A. Schelling; and Diaconessenhuis Leiden — S.A.G.J. Witteveen.

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Related Letters:

Oral Contraceptives and the Risk of Myocardial Infarction
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N Engl J Med 2002; 346:1826-1829, Jun 6, 2002. Correspondence

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