Clinical and metabolic considerations of long-term oral contraceptive use Ian F. Godsland, BA, David Crook, PhD, and Victor Wynn, FRCP, FRCPath London, United Kingdom Newer lower dose formulations are associated with an improved cardiovascular disease risk marker profile, which supports their use for longer periods and among older women . Epidemiologic studies of the newer formulations are limited. Without clinical information, an evaluation of the effects of more recent formulations on metabolic risk markers for cardiovascular disease is useful. In a large cross-sectional study, a reduction in the progestin dose and use of alternative progestins substantiehy reduced the proportion of oral contraceptive users with values associated with an increased risk of cardiovascular disease . No progression in metabolic changes was found by analyzing the effect of the duration of oral contraceptive use. The user's age interacted positively with the oral contraceptive-induced increase in serum triglyceride levels, but there was no interaction of age with the oral contraceptive's effect on oral glucose tolerance, glucose and insulin responses, low-density lipoprotein cholesterol , or high-density lipoprotein subfraction 2 cholesterol levels. (AM J OBSTET GVNECOL 1992;166:1955-63.)
Key words: Cardiovascular disease , progestins, metabolic risk markers. With the introduction of low-dose oral contraceptives and more selective progestins such as desogestrel, gestodene, and norgestimate, the possibility now exists that duration of oral contraceptive use may be prolonged and that oral contraceptive use may be extended to women older than age 35 years . Such use raises specific issues of oral contraceptive safet y. Questions to be ad dressed include whether extending the duration ofcontinuous oral contraceptive use would result in a commensurate increase in any possible risks and whether older women are at increased risk for adverse effects associated with oral contraceptive use compared with their younger counterparts. Recommendations against the use of combination oral contraceptives in women older than 35 years are based on findings from some epidemiologic studies performed during the 1970s, principally the Royal College of General Practitioners' Oral Contraceptive Study. I. 2 This study found that cardiovascular disease was the principal adverse consequence of oral contraceptive use, with risk associated in women older than 35 years who were smokers. Most oral contraceptive formulations included in this and other epidemiologic studies contained 50 f.l.g or more of estrogen. Currently support exists for extending combined oral contraceptive use in older women based on the recognition that, as a result of the introduction of new, lower dose formulations, the risks are likely to ha ve been significantly reduced since the original studies were performed. From the Wynn Institute for M etabolic R esearch. Reprint requests: Ian F. Gods/and, BA, Wynn Institute for Metabolic R esearch, 21 Wellington Rd., London NW8 95Q, United Kingdom. 610137613
Long-term oral contraceptive use and cardiovascular disease Studies of the older medium- and high-dose formulations still provide our only reliable information on long-term oral contraceptive safety and should be taken into account when considering issues related to currently used formulations. Not all studies examined the interactions of duration of use and age of user with risk of cardiovascular disease . Those studies ' :" that showed a positive association between current oral contraceptive use and cardiovascular disease and that specifically addressed interactions with age and duration are listed in Table I. Effects of duration of oral contraceptive use. In the case-control study of mortality from myocardial infarction by Mann et al.," 4 most patients who took oral contraceptives had used them for 2 or more years. Other case-control studies have provided no evidence of an interaction of duration of use with cardiovascu lar disease risks associated with current oral contraceptive use. Likewise, prospective studies have provided little evidence of an effect of duration or use . The 1977 Royal College of General Practitioners' Oral Contraceptive Study described an increased risk of cardiovascular disease with increasing duration of use ," but this was not confirmed in subsequent reports." 2 There was also no evidence of increased risk of cardiovascular disease with prolonged duration of oral contraceptive use in cases in the Oxford/Family Planning Association Cohort.' Effects of age of oral contraceptive user. The casecontrol study of mortality from myocardial infarction of Mann et al.3,4 found increased risk of coronary heart 1955
1956 Godsland, Crook, and Wynn
June 1992 Am J Obstet Gynecol
Table I. Epidemiologic studies that showed an increased risk of ischemic heart disease in current oral contraceptive users and examined the effects of duration of oral contraceptive use and age of the user .Study
Case-control studies Mann and Inman, 1975,' and Mann et al., 19764 Shapiro et al., 1979' Slone et aI., 198 J6 Rosenberg et aI., J980 7 Prospective studies Royal Collegeof General Practitioners' Oral Contraceptive Study 19778 Royal College of General Practitioners' Oral Contraceptive Study 1981' Royal Collegeof General Practitioners' Oral Contraceptive Study 1983 2 Vessey et aI., 19899
Duration effect
I
Age
I---------'------.
effect
Yes
Yes
No No No
No No No
Yes No
Yes* Yes* Yest
No No
*All circulatory diseases. tAli arterial diseases.
disease in women aged 40 to 44 years compared with their younger counterparts. However, the case-control study of survivors of a myocardial infarction of the Boston University Drug Epidemiology Unit" 6 found no increased risk in older compared with younger oral contraceptive users. The concern about a correlation between the user's age and the risk associated with oral contraceptive use stems largely from the findings of the Royal College of General Practitioners' Oral Contraceptive Study. In the 1977 report on this study, a rate ratio of 2.0 was found for mortality from vascular disease in women aged 25 to 34 years who had ever used oral contraceptives, whereas the corresponding rate for users aged 35 to 44 years was 4.5 .8 In the 1981 report on this study, the corresponding figures were 1.6 and 3.3, respectively, among nonsmokers and 3.4 and 4.2 among smokers.' In the 1983 report on arterial disease, the corresponding figures were 1.5 and 1.8, respectively, among nonsmokers and 1.6 and 3.1 among smokers." In the Oxford /Family Planning Association Study most cases of vascular disease were in women older than 35 years of age.!" Effects of previous oral contraceptive use. An important question in long-term oral contraceptive use is whether there is an increased risk of cardiovascular disease in women who are not current users but who have used oral contraceptives in the past. None of the case-control studies that demonstrated an increased risk in current users and in which risk in a past-user group was examined showed an increased risk of cardiovascular disease in previous users. However, onl y one" of these studies was specifically designed to investigate the effects of past use. Among prospective studies, a past-use effect was apparent for cerebrovascular disease but not for ischemic heart disease in the Royal College of General Practitioners' Oral Contraceptive Study.' The Nurses' Health Study" found some evidence of an increased risk of cerebrovascular disease with increasing duration of
previous oral contraceptive use, although this relationship was not significant. In the Oxford/Family Planning Association Study," increased risk of mortality from ischemic heart disease was concentrated among past users, but the authors noted that these women had generally stopped using oral contraceptives because the y developed side effects. Three studies have addressed the issue of a past-use effect in detail. In a case-control study from the Boston University Drug Epidemiology Unit, Slone et al." noted a significant trend in increasing risk of myocardial infarction with duration of previous high-dose oral contraceptive use in women aged 40 to 49 years. This finding was not confirmed by the Nurses' Health Study" or by a subsequent study by Rosenberg et al. '2 The design of the last study reproduced that of the earlier study by Slone et aI., and they concluded that the absence of a past-use effect could have reflected the change toward lower dose oral contraceptives and more selective prescribing.
Metabolic risk markers for cardiovascular disease in long-term oral contraceptive use Information on cardiovascular disease risks associated with the use of oral contraceptives containing less than 50 IJ.g of estrogen is limited , although the available data suggest that risks ma y have been reduced. 13. '4 Littie is known of how the user's age or duration of use interact with any risks associated with these low-dose formulations. The risks associated with low-dose oral contraceptives containing the newly synthesized progestins must also be evaluated. The difficulties in performing effective epidemiologic studies on the effects of oral cont r aceptive use and the length of time needed before potential side effects can be confirmed ha ve favored the use of alternative methods of evaluating long-term oral contraceptive safety. The most important method has been the investigation of oral contraceptive-induced bio-
Vol ume 166 Number 6. Pan :i
Long-term oral contracept ive use
1957
3.5
3.0 l!1
. I
2.5
c
Key words: Cardiovascular disease , progestins, metabolic risk markers. With the introduction of low-dose oral contraceptives and more selective progestins such as desogestrel, gestodene, and norgestimate, the possibility now exists that duration of oral contraceptive use may be prolonged and that oral contraceptive use may be extended to women older than age 35 years . Such use raises specific issues of oral contraceptive safet y. Questions to be ad dressed include whether extending the duration ofcontinuous oral contraceptive use would result in a commensurate increase in any possible risks and whether older women are at increased risk for adverse effects associated with oral contraceptive use compared with their younger counterparts. Recommendations against the use of combination oral contraceptives in women older than 35 years are based on findings from some epidemiologic studies performed during the 1970s, principally the Royal College of General Practitioners' Oral Contraceptive Study. I. 2 This study found that cardiovascular disease was the principal adverse consequence of oral contraceptive use, with risk associated in women older than 35 years who were smokers. Most oral contraceptive formulations included in this and other epidemiologic studies contained 50 f.l.g or more of estrogen. Currently support exists for extending combined oral contraceptive use in older women based on the recognition that, as a result of the introduction of new, lower dose formulations, the risks are likely to ha ve been significantly reduced since the original studies were performed. From the Wynn Institute for M etabolic R esearch. Reprint requests: Ian F. Gods/and, BA, Wynn Institute for Metabolic R esearch, 21 Wellington Rd., London NW8 95Q, United Kingdom. 610137613
Long-term oral contraceptive use and cardiovascular disease Studies of the older medium- and high-dose formulations still provide our only reliable information on long-term oral contraceptive safety and should be taken into account when considering issues related to currently used formulations. Not all studies examined the interactions of duration of use and age of user with risk of cardiovascular disease . Those studies ' :" that showed a positive association between current oral contraceptive use and cardiovascular disease and that specifically addressed interactions with age and duration are listed in Table I. Effects of duration of oral contraceptive use. In the case-control study of mortality from myocardial infarction by Mann et al.," 4 most patients who took oral contraceptives had used them for 2 or more years. Other case-control studies have provided no evidence of an interaction of duration of use with cardiovascu lar disease risks associated with current oral contraceptive use. Likewise, prospective studies have provided little evidence of an effect of duration or use . The 1977 Royal College of General Practitioners' Oral Contraceptive Study described an increased risk of cardiovascular disease with increasing duration of use ," but this was not confirmed in subsequent reports." 2 There was also no evidence of increased risk of cardiovascular disease with prolonged duration of oral contraceptive use in cases in the Oxford/Family Planning Association Cohort.' Effects of age of oral contraceptive user. The casecontrol study of mortality from myocardial infarction of Mann et al.3,4 found increased risk of coronary heart 1955
1956 Godsland, Crook, and Wynn
June 1992 Am J Obstet Gynecol
Table I. Epidemiologic studies that showed an increased risk of ischemic heart disease in current oral contraceptive users and examined the effects of duration of oral contraceptive use and age of the user .Study
Case-control studies Mann and Inman, 1975,' and Mann et al., 19764 Shapiro et al., 1979' Slone et aI., 198 J6 Rosenberg et aI., J980 7 Prospective studies Royal Collegeof General Practitioners' Oral Contraceptive Study 19778 Royal College of General Practitioners' Oral Contraceptive Study 1981' Royal Collegeof General Practitioners' Oral Contraceptive Study 1983 2 Vessey et aI., 19899
Duration effect
I
Age
I---------'------.
effect
Yes
Yes
No No No
No No No
Yes No
Yes* Yes* Yest
No No
*All circulatory diseases. tAli arterial diseases.
disease in women aged 40 to 44 years compared with their younger counterparts. However, the case-control study of survivors of a myocardial infarction of the Boston University Drug Epidemiology Unit" 6 found no increased risk in older compared with younger oral contraceptive users. The concern about a correlation between the user's age and the risk associated with oral contraceptive use stems largely from the findings of the Royal College of General Practitioners' Oral Contraceptive Study. In the 1977 report on this study, a rate ratio of 2.0 was found for mortality from vascular disease in women aged 25 to 34 years who had ever used oral contraceptives, whereas the corresponding rate for users aged 35 to 44 years was 4.5 .8 In the 1981 report on this study, the corresponding figures were 1.6 and 3.3, respectively, among nonsmokers and 3.4 and 4.2 among smokers.' In the 1983 report on arterial disease, the corresponding figures were 1.5 and 1.8, respectively, among nonsmokers and 1.6 and 3.1 among smokers." In the Oxford /Family Planning Association Study most cases of vascular disease were in women older than 35 years of age.!" Effects of previous oral contraceptive use. An important question in long-term oral contraceptive use is whether there is an increased risk of cardiovascular disease in women who are not current users but who have used oral contraceptives in the past. None of the case-control studies that demonstrated an increased risk in current users and in which risk in a past-user group was examined showed an increased risk of cardiovascular disease in previous users. However, onl y one" of these studies was specifically designed to investigate the effects of past use. Among prospective studies, a past-use effect was apparent for cerebrovascular disease but not for ischemic heart disease in the Royal College of General Practitioners' Oral Contraceptive Study.' The Nurses' Health Study" found some evidence of an increased risk of cerebrovascular disease with increasing duration of
previous oral contraceptive use, although this relationship was not significant. In the Oxford/Family Planning Association Study," increased risk of mortality from ischemic heart disease was concentrated among past users, but the authors noted that these women had generally stopped using oral contraceptives because the y developed side effects. Three studies have addressed the issue of a past-use effect in detail. In a case-control study from the Boston University Drug Epidemiology Unit, Slone et al." noted a significant trend in increasing risk of myocardial infarction with duration of previous high-dose oral contraceptive use in women aged 40 to 49 years. This finding was not confirmed by the Nurses' Health Study" or by a subsequent study by Rosenberg et al. '2 The design of the last study reproduced that of the earlier study by Slone et aI., and they concluded that the absence of a past-use effect could have reflected the change toward lower dose oral contraceptives and more selective prescribing.
Metabolic risk markers for cardiovascular disease in long-term oral contraceptive use Information on cardiovascular disease risks associated with the use of oral contraceptives containing less than 50 IJ.g of estrogen is limited , although the available data suggest that risks ma y have been reduced. 13. '4 Littie is known of how the user's age or duration of use interact with any risks associated with these low-dose formulations. The risks associated with low-dose oral contraceptives containing the newly synthesized progestins must also be evaluated. The difficulties in performing effective epidemiologic studies on the effects of oral cont r aceptive use and the length of time needed before potential side effects can be confirmed ha ve favored the use of alternative methods of evaluating long-term oral contraceptive safety. The most important method has been the investigation of oral contraceptive-induced bio-
Vol ume 166 Number 6. Pan :i
Long-term oral contracept ive use
1957
3.5
3.0 l!1
. I
2.5
c
