A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women

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1 CONTRACEPTION A prospective study of oral contraceptive use and risk of myocardial infarction among Swedish women Karen L. Margolis, M.D., a Hans-Olov Adami, M.D., b Juhua Luo, M.S., b Weimin Ye, M.D., b and Elisabete Weiderpass, M.D. b,c a HealthPartners Research Foundation, Minneapolis, Minnesota; b Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; and c The Cancer Registry of Norway, Oslo, Norway Objective: To determine the risk for incident myocardial infarction (MI) in women exposed to modern formulations of oral contraceptives (OCs). Design: Population-based, prospective cohort study begun in 1991 with follow-up through 2002 for an average of 11 years. Patient(s): A total of 48,321 Swedish women aged randomly selected from the population residing in the Uppsala Health Care Region of Sweden in Main Outcome Measure(s): Fatal and nonfatal MI ascertained through linkages with nationwide health registries for death, hospitalization, and emigration. Result(s): There were 214 incident cases of MI. Compared with never users, neither former (relative risk, 1.0; 95% confidence interval, ) nor current (relative risk, 0.7; 95% confidence interval, ) OC users at study enrollment had an elevated risk of future MI in models adjusted for coronary heart disease risk factors. Risk of MI was not elevated by prolonged use or in subgroups defined by characteristics of the women or types of OC. Conclusion(s): Use of OC was not associated with an increased risk of MI in this prospective study, in which most current users of OC were taking low-dose estrogen and second- or third-generation progestins. (Fertil Steril Ò 2007;88: Ó2007 by American Society for Reproductive Medicine.) Key Words: Oral contraceptives, coronary heart disease, myocardial infarction Received August 10, 2006; revised and accepted November 22, Supported by the Swedish Council for Planning and coordination of Research, Swedish Cancer Society, Swedish Medical Products Agency, Organon, Pharmacia, and Schering-Plough. Dr. Margolis received support from awards from the National Heart, Lung and Blood Institute (K23 HL03996) and from the University of Minnesota International Medical Education and Research Program. None of the funders was involved in the design or conduct of the study; collection, management, analysis, or interpretation of data; or preparation, review, or approval of the manuscript. Correspondence to: Karen L. Margolis, M.D., M.P.H., HealthPartners Research Foundation, P.O. Box 1524, Mail Stop 21111R, Minneapolis, MN (FAX: ; Karen.L.Margolis@ HealthPartners.com). As one of the most popular methods of birth control, oral contraceptives (OCs) are used by more than 100 million women worldwide, including large numbers of women in the developing world (1). In the United States, 80% of all women born since 1945 have used OCs, and the proportion is similar or higher among European women (1, 2). Ever since the first OC became available in the 1960s, adverse cardiovascular effects and multiplicative effects in smokers have been reported (3 5). Although modern formulations of OCs incorporate substantially lower estrogen doses and newer progestins with fewer adverse effects on lipids, persistent concerns about an increase in coronary heart disease (CHD) events (including nonfatal myocardial infarction [MI] and CHD-related death) remain unresolved. Although the absolute incidence of MI is low in young women, even a small increase in risk could have public health importance because of the high prevalence of OC use. Furthermore, women in their late 30s and 40s are increasingly frequent users of OCs: in 2002, 14% of women aged reported current use of OCs, which is an increase from the 4% reported in 1995 (6, 7). Few prospective studies have compared the risk of CHD events in current or past users of OCs with that of nonusers, and all pertain to OC use in the 1970s and 1980s, when pills commonly contained high-dose estrogen (8 12). These have been fairly consistent in showing an elevation of MI risk among current OC users who were smokers (8 11), and some studies showed an increased MI risk among past OC users who were smokers (8, 10). Case-control studies reporting data collected since lower dose estrogen pills came into common use have been contradictory, with some showing modest elevation in risk among nonsmokers and others showing no excess risk even among smokers (13 21). The Swedish Women s Lifestyle and Health Cohort Study, a populationbased, prospective study started in 1991, is specifically designed to examine the long-term health effects of hormonal contraceptives. We analyzed data from this large study to 310 Fertility and Sterility â Vol. 88, No. 2, August /07/$32.00 Copyright ª2007 American Society for Reproductive Medicine, Published by Elsevier Inc. doi: /j.fertnstert

2 examine the risk for incident MI in women exposed mainly to low-dose formulations of OCs during their reproductive years. METHODS Study Participants and Data Collection The Women s Lifestyle and Health Study, a prospective cohort study of 106,841 Norwegian and Swedish women aged in Norway and Sweden, has been described in detail elsewhere (22, 23). This analysis is restricted to the Swedish women, who were monitored with regard to vital status, emigration, and incidence of fatal and nonfatal MI since The source population in Sweden consisted of all women who were years old and resided in the Uppsala Health Care Region in Women were randomly selected from the populations within four 5-year birth cohorts (ages 30 34, 35 39, 40 44, and years). A total of 96,000 women were invited to participate, and 49,259 (51.3 %) returned the questionnaire. Although the characteristics of the nonrespondents are not known, the response rate represents a much higher proportion of the invited population than is typically enrolled in population-based prospective cohort studies. All of the women provided informed consent before participating in the study. The responsible data inspection boards and ethics committees approved the study design. Exposure and covariate data in the cohort are based on selfreported information collected in a questionnaire administered at cohort enrollment. The questionnaire included questions about demographic characteristics, medical history, reproductive history, active and passive smoking exposure, alcohol intake, physical activity, height, weight, and a detailed assessment of contraceptive use. To facilitate recall, a color brochure with pictures of almost all contraceptive pill packages ever sold in Sweden was sent to all women. Questions about exposure to hormonal contraceptives included summary measures, such as ever having used an OC, current OC use, total duration of use, and age at first use. Detailed information was also collected about each specific period of use, defined as any continuous use of one specific hormonal contraceptive brand. Up to 10 different periods of use were reported, with questions about age at starting, duration of use, and brand name. Based on a combination of the summary measures and the detailed information about each period of use, we calculated the total duration of use, time since last use, time since first use, and current use (defined as use within the previous year). We further classified OC types according to combined OC versus progestin-only pill, estrogen dose (low-dose [defined as <50 mg ethinyl estradiol or <75 mg mestranol] vs. high dose), monophasic versus sequential, and generation of progestin. Following the classification of Keeling (5), norgestrel and levonorgestrel were designated as second-generation progestins and desogestrel was designated as third generation. The following progestins were designated as first generation: norethisterone (norethindrone), norethynodrel, lynestrenol, ethynodiol acetate, and chormadinone acetate. Megestrol, quingestanol, and cyproterone acetate were classified as other progestins. Follow-up Follow-up of the cohort was achieved through linkages with existing nationwide health registers. Because each resident in Sweden is assigned a unique national registration number, one can link the data from the cohort with these registers for virtually complete follow-up with respect to death, emigration, and MI. Information on death and emigration was collected through linkage to Statistics Sweden. Information on fatal and nonfatal MI was collected through linkage to the National Causes of Death Register and the National Hospital Discharge Register (ICD-9 code 410 or ICD-10 code I21 or I22 for acute MI). This method of ascertainment has been shown to be both sensitive and specific for hospitalized and fatal MI (24). During , 360,000 cases of acute MI were identified, of which 39% were in women. A random sample of 2065 medical records of patients aged with a discharge ICD-9 code for acute MI [410] or ischemic heart disease [ ] was selected. Of these, 1848 records could be obtained and adjudicated based on a standard definition combining autopsy results, electrocardiogram findings, markers of myocardial injury, and symptoms. In 1995, 95.4% of cases coded as ICD9 410 were classified as definite or probable acute MI. The corresponding proportion in 1987 was 94.4%. Among cases reported as ICD-9 codes , 2.9% met the criteria for acute MI. The start of follow-up was defined as the date of return of the questionnaire during Person-years were calculated from the start of follow-up to the primary diagnosis of fatal or nonfatal MI, date of emigration or non-chd death, or the end of follow-up (December 31, 2002), whichever came first. The mean follow-up was 11.0 years. The responsible data-monitoring boards and ethics committees approved the study design, and all women gave informed consent before participating in the study. Statistical Analysis From the initial cohort, we excluded 204 women with a selfreported history of MI or stroke at enrollment. We further excluded 28 women for whom linkage data with the National Hospital Discharge Register showed hospitalization for MI before enrollment, 663 women who were missing information on use of OC or smoking, and 43 women who reported only use of injectable or implanted progestin-only contraceptives. Thus, the final analysis was based on data from 48,321 women. The relation between OC use and MI was assessed using time-to-event analyses. Proportional hazard models (Proc PHREG, SAS Version 9.1; SAS Institute, Inc., Cary, NC) were used to estimate the hazard ratio as a measure of relative risk (RR) and with 95% confidence interval (CI), controlling for potential confounders. In each comparison, OC never users were used as the reference. The following covariates assessed at enrollment Fertility and Sterility â 311

3 were considered as potential confounders of the association between OC use and MI and included in multivariable analyses: age, years of education, body mass index (BMI), smoking status (never, former, current, and pack-years for former and current smokers), history of passive smoking, alcohol intake (grams/day), physical activity (very low, low, moderate, high, very high), history of hypertension, history of diabetes, ever having been told by a physician not to take OCs, and menopausal status at enrollment. To assess possible effect modification, we first estimated hazard ratios comparing never, past, and current OC use and stratified models by smoking status, hypertension, diabetes, estrogen dose, and type of progestin. We then assessed effect modification on a multiplicative scale by modeling interaction terms and calculating log-likelihood ratio tests to assess whether interaction terms were significantly different than 0. We were unable to examine OC use as a time-dependent predictor as we did not have information on postenrollment OC use. Many current users discontinued OC use during 11 years of follow-up but were probably less likely to do so early in the follow-up period. Therefore, to assess the risk of early versus late MI among never users, former users, and current OC users, we examined time-to-event curves among all cases of MI and compared them using the Wilcoxon test. RESULTS Approximately 17% of the study participants had never used OCs, 68% were former users, and 14% were current users at enrollment (Table 1). More than half of current users were aged 35 and older. Compared with never users, current OC users were younger, leaner, more educated, drank more alcohol, were more likely to smoke and have been exposed to second-hand smoke, were more likely to report high levels of physical activity, were less likely to be menopausal, and were less likely to have hypertension or diabetes. For most variables, former users had characteristics intermediate between current and never users, except that they were the most likely to smoke and had the highest alcohol intake. Most OC users began using them while in their teens and early 20s (Table 2). Most former users had used OCs for less than 10 years, while most current users had used them for more than 10 years. Few women (15% of former users and 7% of current users) had ever been told to stop taking OCs by a physician. Among these women, 33% were former smokers, 33% were current smokers, 26% had hypertension, and 3% had diabetes. The majority of women had exclusively used combined OCs, but a substantial proportion of women had used both combined OCs and progestin-only pills. Few women had used progestin-only pills exclusively, but 28% of current OC users took a progestin-only preparation. About TABLE 1 Baseline characteristics of women enrolled in the Women s Lifestyle and Health Study, by oral contraceptive use. Never used Former user Current user Subjects, n (%) 8013 (16.6) 33,507 (69.3) 6801 (14.1) Age at enrollment: Mean, years , % , % , % , % Mean BMI (kg/m 2 ) Mean years of education Mean alcohol use, g/day Ever smoking, % Current smoking, % Passive smoking, % Physical activity, %: Very low or low Normal High or very high Menopausal, % Hypertension, % Diabetes, % Margolis et al. Oral contraceptives and myocardial infarction Vol. 88, No. 2, August 2007

4 TABLE 2 Description of patterns of oral contraceptive use for past and current users. Former user, % Current user, % Age at first use, years: < þ Duration of use, years: < þ Doctor ever recommended to stop use Used for a reason other than to prevent pregnancy Type of OCs in ever users: Progestin only Combined OCs only Mixed Generation of progestin in ever combined OC users: Second or third only All others Estrogen dose in ever combined OC users: Only low dose All others Type of contraceptive in current users: Progestin-only (including injected or implanted) 27.9 Combined OCs 72.1 Generation of progestin in current combined OC users: Second or third 81.9 First 18.1 Estrogen dose in current combined OC users: Low dose 81.7 High dose 18.3 one-third of all users had only used combined OCs with second- or third-generation progestins, but more than 80% of current users were taking a combined OC containing a second- or third-generation progestin. A minority of women had used only low-dose estrogen in combined OCs, but more than 80% of current users were taking a combined OC containing low-dose estrogen. There were 190 cases of non-fatal MI and 24 deaths due to MI (214 total events) among women included in this analysis during 11.0 years of follow-up. Among the CHD risk factors, significant predictors of MI included age (RR, 1.16 per year; 95% CI, ), education (RR, 0.4; 95% CI, for >16 years vs. <10 years), BMI (RR, 2.2; 95% CI, for BMI >30 vs. <22), smoking (RR, 4.3; 96% CI, for >20 pack-years vs. <5 pack-years), hypertension (RR, 2.5; 95% CI, ), and diabetes (RR, 6.7; 95% CI, ). As shown in Table 3, compared with never users, women who had ever used OC did not have an elevated risk of MI (RR, 1.0; 95% CI, ). This was true for both former and current users at enrollment, and the risk was similar in models adjusted only for age and for multiple CHD risk factors. The risk of MI was also not elevated in current users compared with former users (RR, 0.8; 95% CI, ). Comparison of the time-to-event curves showed no difference for never users, former users, and current OC users for developing fatal or nonfatal MI over 11 years of follow-up (Fig. 1). There was no effect modification by hypertension, diabetes, or smoking status. Of the 214 MIs, 11 occurred in women who were current OC users at enrollment, of whom five also reported current smoking. In stratified analyses, the adjusted risk of MI among current OC users who also currently smoked was not significantly elevated, although the CI was wide (RR, 0.7; 95% CI, ). Risk of MI was not elevated Fertility and Sterility â 313

5 TABLE 3 Relative risk of fatal or nonfatal myocardial infarction among oral contraceptive users, according to different patterns of use. Variable Person-years MI cases Age-adjusted RR (95% CI) Multivariate RR (95% CI)* Never used OCs 87, Reference Reference Ever user OCs: 443, ( ) 1.0 ( ) Former user 368, ( ) 1.0 ( ) Current user 75, ( ) 0.7 ( ) Age at first use, years: <20 249, ( ) 0.8 ( ) , ( ) 0.9 ( ) , ( ) 1.2 ( ) 30þ 17, ( ) 1.0 ( ) P for trend.9.7 Duration of use, years: <5 189, ( ) 0.9 ( ) , ( ) 1.0 ( ) , ( ) 1.1 ( ) 15þ 46, ( ) 0.7 ( ) P for trend.6.7 Ever recommended to stop use?: No 373, ( ) 0.8 ( ) Yes 62, ( ) 1.4 ( ) Used for a reason other than to prevent pregnancy?: No 347, ( ) 1.0 ( ) Yes 93, ( ) 1.0 ( ) * Included in multivariable model: age, years of education, body mass index, smoking status (never, former, current, and pack-years for former, and current smokers), history of passive smoking, alcohol intake, physical activity, history or hypertension, history of diabetes, and menopausal status at enrollment. FIGURE 1 Time to event for developing MI among all cases by OC status. in subgroups defined by age at first use, duration of use, and use for reasons other than to prevent pregnancy (Table 3). However, women who had been advised to stop OC use by a physician did have an elevated risk of MI (RR, 1.4; 95% CI, ), even after adjusting for a history of smoking, hypertension, or diabetes. Compared with never users, there was no elevation in MI risk by type of OC, generation of progestin, or estrogen dose among all users. Although power was low and CIs were wide, there was also no evidence of elevated MI risk by type of OC, progestin, or estrogen dose among current users. DISCUSSION These data from a large population-based, prospective cohort study conducted in the era of contemporary, mostly low-dose OCs suggest no increase in the risk of MI among current or past users or any trend by duration of use up to 15 or more years. Although power was lower for subgroup comparisons, no pattern of use or type of OC was associated with increased 314 Margolis et al. Oral contraceptives and myocardial infarction Vol. 88, No. 2, August 2007

6 risk. The moderate excess risk among women who were recommended to stop OC use is likely due to physicians having more detailed information than our questionnaires to assess cardiovascular risk rather than to a causal role of OCs. For example, elevated blood pressure while on OCs and family history of CHD were not captured by our questionnaire. The largest cohort study published to date on hormonal contraceptives and risk of cardiovascular diseases uses data on 119,061 women enrolled in the Nurses Health Study in 1976 and followed up prospectively for 8 years (9). This study showed no association between past OC use and MI or stroke, but current OC users had a 2.5-fold elevated MI risk (95% CI, ). As in the Women s Lifestyle and Health Study, there were few events among women who were classified as current OC users (n ¼10 MIs). Most of these (n ¼ 7) were noted to have occurred in smokers, but no formal statistical analysis was performed on the interaction between smoking and OC use because of the small number of events. Another study from this cohort showed no increase in cardiovascular mortality or total mortality in ever or current OC users (25). Some smaller prospective studies found an elevated risk of MI in current OC users that was confined to women who smoked (8, 10). In the Royal College of General Practitioners nested case-control study conducted between 1968 and 1987, current use of OC increased the risk of MI particularly among heavy smokers: smokers of <15 cigarettes/day had a 3.5-fold (95% CI, ) elevation, smokers of 15 or more cigarettes/day had a 20.8-fold ( ) increase in risk, and nonsmokers had no increase in risk during OC use. Previous use of OCs influenced the risk of MI only in the heavy smokers (RR, 4.3; 95% CI, ) (8). A second British study followed 17,000 women from 1968 to 1994, during which time 85 MIs occurred. There was a four-fold increased risk of MI in heavy smokers who were current or past OC users, while lighter smokers and nonsmokers showed no increased risks with OC use (10). Similarly, a small Finnish cohort study found that women currently taking OCs had a 1.3-fold (95% CI, ) risk of developing MI compared with those who did not (11). Women who both smoked and used OC had a 7.2-fold (95% CI, ) risk of MI compared with nonsmokers and nonusers of OC. The results of recent case-control studies could help to shed light on the CHD risks associated with current use of more modern formulations of OCs, but these have been somewhat contradictory. Of nine such studies, only three found significant elevations in the risk of MI in the range of 2- to 5-fold with current OC use (15, 19, 21), while the remaining studies did not (13, 14, 16 18, 20). As in the cohort studies, there was little indication of MI risk associated with past use of OCs and evidence of powerful interaction with smoking. A study conducted in the Netherlands (19) found a doubling of MI risk in OC users even among nonsmokers, while smokers had a 14-fold elevation in risk compared with nonsmokers who did not use OCs. This study and one other study (15) suggested that the risk was elevated in users of OC containing second-generation progestins but not thirdgeneration progestins, although the confidence intervals for the risks with the two types of progestins overlapped. The strengths of our study include its prospective design, large size, and complete follow-up using highly reliable sources of data on CHD outcomes. In 531,402 person-years of follow-up, we observed over 200 MIs, a number surpassed only by one cohort study published to date (9). The study had sufficient power to detect elevated risk of MI with known CHD risk factors. However, this analysis has several limitations that should be taken into consideration in interpreting the results. The results pertain only to MI and not to other forms of cardiovascular disease, such as stroke or venous thromboembolism. The data on OC use were self-reported and collected by a mailed questionnaire. Previous studies have suggested that self-report of OC use by women is reasonably accurate, particularly when supplemented by visual memory aids (26, 27). Owing to the age of the study population, a relatively small proportion currently used OCs; thus the present study did not have enough power to discern differences between small subgroups, such as current users of second- and third-generation progestin-containing pills. Most importantly, OC exposure data were collected at enrollment only, and we lack information about ongoing OC use during the follow-up period. Such misclassification could attenuate the strength of any true association by classifying as current users women who had discontinued OC use during follow-up. Although the term current OC use calls attention to it in this study, this type limitation is often present in prospective cohort studies of modifiable cardiovascular risk factors. For example, blood pressure, diet, lipids, inflammatory markers, and other biomarkers are commonly only measured once at enrollment in the cohort. Nevertheless, since myocardial infarction in OC users is thought to be induced primarily by hypercoagulabilty and subsequent thrombosis rather than through atherosclerotic mechanisms, MI risk may wane rapidly upon discontinuation of OC. Of interest in this regard is a recent retrospective study that showed less angiographic coronary artery disease in postmenopausal women who had previously used OCs, even after adjusting for known risk factors (28). Mitigating the concern about misclassification, comparison of survival curves did not reveal any evidence of a higher rate of MI in current users early in follow-up when exposure misclassification was presumably low. We conclude that current and past use of OCs was not associated with an increased risk of MI in this study of women aged at enrollment, in which most current users of OCs were taking low-dose estrogen and second- or thirdgeneration progestins. Although the data suggest no increased risk, a conservative interpretation taking into account the upper 95% CI is that it is very unlikely that coronary risk is increased by more than 50%. Although the absolute risks of coronary events are low in women in this age group, the increasing use of OC in the later reproductive and Fertility and Sterility â 315

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