Consensus conference on combination oral contraceptives and cardiovascular disease.

PIP: At the June 1998 conference of the International Federation of Fertility Societies (IFFS), a consensus was reached that there is no reason to advise selective prescribing of oral contraceptives (OCs) containing different progestins on the basis of their effects on cardiovascular disease. All currently available low-dose OCs, regardless of their progestin component, are more beneficial for a woman's short- or long-term health than the alternative of use of no contraception or use of a less effective method. The usual precautions in selecting appropriate candidates for OC use should be applied. This consensus was reached after several investigators presented the results of their studies on OC use and cardiovascular risk to an IFFS panel. Consolidation of the available research evidence produced annual cardiovascular mortality rates per 100,000 among women 15-24 years old of 1.2 in OC non-users, 2.1 in users of second-generation OCs, and 1.8-2.3 in users of third-generation OCs; among women 35-44 years old, these rates were 9.2, 20.4, and 15.5-17.8, respectively.^ieng

Oral contraceptives and myocardial infarction: results of the MICA case-control study.

OBJECTIVES: To determine the association between myocardial infarction and use of different types of oral contraception in young women. DESIGN: Community based case-control study. Data from interviews and general practice records. SETTING: England, Scotland, and Wales. PARTICIPANTS: Cases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice. MAIN OUTCOME MEASURES: Odds ratios for myocardial infarction in current users of all combined oral contraceptives stratified by their progestagen content compared with non-users; current users of third generation versus second generation oral contraceptives. RESULTS: The adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2. 52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day. CONCLUSIONS: There was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

PIP: The association between myocardial infarction and use of oral contraceptives (OCs) was investigated in a case-control study conducted in England, Scotland, and Wales. 448 women 16-44 years old who had suffered an incident myocardial infarction during 1991-95 were identified from general practice records and matched by age and general practice with 1728 healthy controls. 85% of cases were not taking OCs in the 3 months before their myocardial infarction. The adjusted odds ratio (OR) for myocardial infarction was 1.40 (95% confidence interval [CI], 0.78-2.52) for all combined OC users, 1.10 (95% CI, 0.52-2.30) for users of second-generation formulations, and 1.96 (95% CI, 0.87-4.39) for third-generation OCs. Subgroup analysis by progestogen content did not show any significant difference from 1, and there was no effect of duration of OC use. 88% of cases had clinical cardiovascular risk factors or were smokers, or both. The adjusted OR for third-generation vs. second-generation OC users was 1.78 (95% CI, 0.66-4.83). The adjusted OR was 12.5 (95% CI, 7.29-21.5) among women who smoked 20 or more cigarettes a day. These findings indicate that OCs, including third-generation formulations, do not increase a woman's risk of myocardial infarction. Women who are concerned about their cardiovascular health should be urged to stop smoking, however.

Breast cancer risk: perception versus reality.

Evidence that breast cancer is hormonally mediated has fueled women's concern that use of oral contraceptives (OC) will increase their risk of developing the disease. A recent reanalysis of combined worldwide epidemiologic evidence regarding the relationship between breast cancer risk and use of combination OC provides reassurance that there is little or no association between OC use and breast cancer. Ten or more years after discontinuation of OC use, there is no difference in cumulative risk of breast cancer among OC ever-users and never-users. The risk of breast cancer diagnosis is slightly elevated in current OC users and remains slightly elevated until about 10 years after OC discontinuation. Once recency of use is taken into account, other characteristics have little additional effect. There is no increase in breast cancer risk with increasing dose or duration of OC use and no difference in risk related to type of estrogen or progestin used. Moreover, those breast cancers diagnosed in OC ever-users were found to be significantly more likely to be localized than those diagnosed in same-age never-users.

PIP: A recent survey of US women 40-50 years old with no history of breast cancer found that women's perceptions of their risk of developing and dying of breast cancer exceeded the actual risk. Evidence that breast cancer is hormonally mediated has raised concerns that oral contraceptive (OC) use increases a woman's risk of developing the disease. This concern has been fueled by the observation that the increasing diagnosis of breast cancer in many countries has occurred in tandem with widespread OC use. However, a reanalysis by the UK Imperial Cancer Research Fund Epidemiology Unit of worldwide epidemiologic data revealed little or no evidence of a link between OC use and breast cancer. 10 or more years after discontinuation of OCs, there is no difference in cumulative breast cancer risk between OC ever-users and nonusers. Breast cancer risk among ever-users was not affected by duration of OC use, age at first use, parity, family history, or the dose or type of OC. Moreover, breast cancers diagnosed in OC ever-users are significantly less advanced and more likely to be localized to the breast than those in never-users. It may be that current or recent OC users are receiving more breast examinations and therefore have the opportunity for early diagnosis and improved prognosis.

Further insight gained on impact of OC use.

PIP: A 25-year follow-up (1968-93) of the 46,000 British women enrolled in the Royal College of General Practitioners' Oral Contraception (OC) study indicated that OCs exert their main effect on mortality while they are being used and in the 10 years immediately after method discontinuation. By 1993, the median age of women enrolled in the cohort was 49 years. There were 1599 deaths during the follow-up period--945 in women who had ever used OCs and 654 in never-users. Among current and recent (within 10 years) users, the relative risk of death was 0.2 from ovarian cancer, 2.5 from cervical cancer, and 1.9 from cerebrovascular disease. There were no significant excesses or deficits either overall or from any specific cause of death among women who had ended pill use 10 or more years earlier. However, the study lacked adequate statistical power to analyze mortality from specific causes such as ovarian or cervical cancer.^ieng

[Current monophasic hormonal contraception]. / Suvremennata monofazna khormonalna kontratseptsiia.

Data are presented from an investigation of the use of monophasic contraceptive pills chosen by different age groups. Analyses are made of the data obtained from the Bulgarian Association for Family Planning (BAFP) card index for the last two years. Information is given on the number of observed cycles, type of applied contraceptive pill, aims of their application (contraception, treatment of acne, menstrual disturbances etc.), age of patients, as well as any possible adverse effects--change in blood pressure, bodyweight changes, intermenstrual bleeding, hairiness, breast problems, paraclinical changes, etc. The observed cycles show a very small percentage of adverse effects with hormonal contraception, mainly during the first 2 or 3 cycles, with predominance of intermenstrual bleeding. No bodyweight changes or increased hairiness were observed.

PIP: The data for this analysis were obtained from the records of the Bulgarian Association for Family Planning (BAFP); the data covered a period of 3 years and were for 593 women with a total menstrual cycle of 3132. The most frequently used monophasic oral contraceptives were Cilest (containing norgestimate and ethinyl estradiol), used by 233 women, Marvelon (containing desogestrel and ethinyl estradiol), used by 154 women, Microgynon FE, used by 117 women, and Nordette (containing levonorgestrel and ethinyl estradiol), used by 89 women. The preparations were used mainly for contraception, but some women used them for menstrual regulation (27 women used Nordette for this purpose and so did 25 women use Marvelon for such a purpose), and a small percentage of the women used them for used dysmenorrhea. 103 (43.2%) women who used Cilest were in the 14-19 age group, while 106 (45.4%) of them were in the 20-25 age group. In the 14-19 age group 20 (17.2%) used Microgynon, 18 (20.2%) used Nordette, and 60 (38.8%) relied on Marvelon. In the 20-25 age group the respective figures were 79 (67.2%) for Microgynon, 40 (44.9%) for Nordette, and 67 (42.5%) for Marvelon. Some of the unfavorable metabolic effects of oral contraceptives included the increase of LDL and the reduction of HDL levels and androgenic effects. The most frequent side effect was intermenstrual bleeding, of which there were 19 cases for Cilest, 7 for Microgynon, 5 for Nordette, and 11 for Marvelon. Menstruation was prolonged in 4 women using Cilest and in 5 using Marvelon. 5 women using Cilest, 2 using Microgynon, and 2 using Nordette had headache. Other adverse effects included episodes of galactorrhea, discomfort, mastopathy, and bloating in the stomach. These effects did not pose a risk to general or reproductive health and did not justify discontinuation of use for these preparations.

Cardiovascular safety of oral contraceptives. What has changed in the last decade?

PIP: As a result of careful patient selection, the cardiovascular safety of oral contraceptives (OCs) has improved dramatically in the past decade. The incidence of stroke and myocardial infarction is exceedingly low among women who use OCs containing 35 mcg or less of ethinyl estradiol, and formulations containing under 50 mcg of estrogen account for almost all current use in the US. This article reviews the epidemiologic data on use of OCs of varying steroid dosages on the risks of myocardial infarction, hemorrhagic and ischemic stroke, and venous thromboembolism. Although four studies published since 1995 have suggested that OCs containing desogestrel or gestodene increase the risk of venous thromboembolism above that associated with levonorgestrel, these findings are likely due to prescribing bias and differences in the duration of use. The greatest risk of an arterial cardiovascular event comes from smoking while taking OCs.^ieng

Uniqueness of oral contraceptive progestins.

PIP: Gonane progestins are more potent and, except for levonorgestrel, less androgenic than the estrane progestins that preceded them. The current, informal method for classifying oral contraceptives (OCs) as old, first generation, or second generation on the basis of their date of introduction obscures the fact that each of the gonane progestins has unique biologic properties. Recommended, instead, is the classification of OCs according to their level of androgenicity. Under such a system, norgestimate, desogestrel, and monophasic norethindrone (0.4-0.5 mg) would fall into the low category. Triphasic levonorgestrel, norethindrone (1.0 mg), norethindrone acetate (1.0 mg), and ethynodiol diacetate (1.0 mg) would be classified as having medium androgenicity, while norgestrel (0.3 mg), norethindrone acetate (1.5-2.5 mg), and levonorgestrel (0.15 mg) would fall into the high androgenicity category.^ieng

Effect of oral contraceptive progestins on serum copper concentration.

OBJECTIVES: Recent epidemiologic studies have shown an increased mortality from cardiovascular diseases in people with higher serum copper levels. Even though higher serum copper concentration in women using oral contraceptives is well known, there is still uncertainty about the influence of newer progestin compounds in oral contraceptives on serum copper concentration. This issue is of particular interest in the light of recent findings of an increased risk of venous thromboembolism in users of oral contraceptives containing newer progestins like desogestrel compared to users of other oral contraceptives. DESIGN: Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. SETTING: National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. SUBJECTS: Nonpregnant and nonlactating women aged 18-44 y (n = 610). RESULTS: Overall, the use of oral contraceptives was positively associated with serum copper concentration in by bi- and multivariable linear regression models with log-transformed values of serum copper concentration as dependend variable and oral contraceptive preparations and potential confounding variables as independent variables. Serum copper concentration in women using oral contraceptives varied more strongly by different progestin compounds than by estrogen contents. The highest increase of serum copper was seen in women using oral contraceptives containing antiandrogen progestins (55%; 95% CI: 37-76%), followed by desogestrel (46%; 95% CI: 36-56%), norethisteron/lynestrenol (42%; 95% CI: 29-57%), and levonorgestrel (34%; 95% CI: 24-45%). CONCLUSION: While elevated serum copper concentration was found in users of all types of oral contraceptives, elevation was more pronounced among women taking oral contraceptives with antiandrogen effective progestins like antiandrogens or third generation oral contraceptives containing desogestrel. Further investigation is required to shed light on the possible role of high serum copper concentration in increasing cardiovascular or thrombotic risk of women using oral contraceptives.

PIP: High serum copper concentration--a well-known effect of oral contraceptive (OC) use--has been linked to increased mortality from cardiovascular disease. The influence of OCs containing newer progestins has not been investigated, however. This concern was addressed in a 1987-88 cross-sectional epidemiologic study of 610 nonpregnant, nonlactating West German women 18-44 years of age. 195 women (32.1%) were current OC users, but only 152 of these women were able to cite the name of the formulation they were taking. In 70% of cases, the OC contained less than 45 mcg of ethylestradiol (median dose, 32.4 mcg). The most common progestin components were desogestrel (41%) and levonorgestrel (30%). Mean serum copper concentration was higher among users of all types of OCs than among non-users, but this concentration varied more strongly according to the OC's progestin compound than its estrogen content. The greatest increase in serum copper (55% compared with non-users) was recorded in users of OCs containing anti-androgen progestins, followed by desogestrel (46%), norethisterone/lynestrenol (42%), and levonorgestrel (34%). The increase in serum copper was more pronounced in women taking OCs containing 45 mcg or less of ethylestradiol than in users of OCs with a high estrogen dose. In the regression models, the different progestin compounds alone explained 28% of the total variance in serum copper concentration. Further investigation of OC-induced increases in serum copper concentration and their impact on cardiovascular risk are warranted.

Two-year treatment with oral contraceptives in hyperprolactinemic patients.

The aim of this prospective study was the follow-up for 2 years in symptoms, serum prolactin (PRL) levels, and radiological aspects of a group of young patients using oral contraceptives (OC) with hyperprolactinemia. A total of 16 hyperprolactinemic women (eight with idiopathic hyperprolactinemia and eight with pituitary microadenoma) who started OC use were admitted in the study. After 2 years of OC use, the assessable patients showed a nonsignificant decrease in plasma PRL level (26.8 +/- 29.4 micrograms/mL, range 4.2-97.1 micrograms/mL vs 56.3 +/- 31.5 micrograms/mL, range 23.5-144 micrograms/mL). No patient experienced any radiological changes during OC treatment. In conclusion, although the number of observations is limited, the data suggest that after 2 years of follow-up, no harmful effect of OC use was observed in these patients.

PIP: Recent case-control studies have failed to document any growth of pituitary adenomas following oral contraceptive (OC) use. The present study, involving 16 hyperprolactinemic OC users (8 with idiopathic and 8 with pituitary microadenoma) from Milan, Italy, also suggested exogenous estrogen has no harmful effects on these patients. Study participants underwent two blood collections before OC initiation for measurement of basal prolactin levels as well as a pituitary computed tomography or nuclear magnetic resonance scan. During OC use, prolactin measurements were taken between days 5-10 during cycles 6, 12, 18, and 24. At the end of the 24-month treatment period, all women underwent a second radiologic examination. After 2 years of OC use, women showed a nonsignificant decrease in plasma serum prolactin levels (median, 26.8 +or- 29.4 mcg/ml; range, 23.5-144 mcg/ml). No radiologic changes occurred. No patient experienced a prolactinoma enlargement during OC use. Despite a lack of evidence, OC administration is often considered contraindicated in hyperprolactinemic women.

Venous thromboembolism and the pill. Learning from the past: a response from The Committee on Safety of Medicines.

PIP: The suggestion, raised by Benagiano, that regulatory authorities should act only after publication of the relevant data would have serious public safety consequences. Where possible, the UK Committee on Safety of Medicines (of which the author is chair) coordinates its regulatory positions with publication of the relevant data. For example, the Committee was able to ensure that publication of the meta-analysis of hormone replacement therapy and breast cancer risk coincided with advice to prescribers and patients through use of the Epinet system and the Internet. In the case of findings of a venous thromboembolism risk associated with use of third-generation oral contraceptives, however, regulatory action had to be taken in advance of study publication. The urgency was based on the expectation that 100-150 cases of venous thromboembolism and 1-2 deaths would be prevented per year by careful prescribing of these formulations. The recommendation that regulatory authorities delay action further ignores the fact that drug regulation incorporates a process of peer review far more rigorous than that of any scientific journal.^ieng

Oral contraceptives and thrombosis: an overview of study methods and recent results.

Studies of the associations between oral contraceptives and cardiovascular disease are limited by the extreme rarity of these problems among young women. There are no randomized, controlled trials, and the large, prospective cohort studies only have data regarding older oral contraceptive formulations that are now little used. Historical cohort studies that use record-linkage techniques to analyze data from computerized databases represent a new approach to assessing oral contraceptive use and thrombosis. The largest new studies, with the most sophisticated analyses, use the case-control design. A surprising result of the new studies was a difference in risk of thrombosis according to progestin type. Because these are observational rather than randomized studies, clinical factors influence the choice of oral contraceptive and may bias the study results. Controversy about the surprising results has stimulated additional analyses and critical reviews in an attempt to explain the associations.

PIP: This article discusses methodologic aspects of recent studies on oral contraceptive (OC) use and thrombosis. Because of the extreme rarity of cardiovascular disease among young women, no studies of cardiovascular outcomes have employed a randomized, controlled trial design. Rather, all knowledge of OC risks comes from observational studies. Although case-control studies have suggested a difference in thrombosis risk according to progestin type, clinical factors that influence the choice of OC may bias the results. Historical cohort studies based on record-linkage techniques to analyze data from computerized databases represent a promising new approach for assessing the thrombosis risk of OCs. Overall, epidemiologic studies are less useful for subtle, weak associations where the relative risk is close to 1--the case with the most recent round of studies on the OC-thrombosis association. A balanced assessment of the differential values of various combination OCs would require that all the risks and benefits be considered on a formulation-by-formulation basis.

Bias versus causality: interpreting recent evidence of oral contraceptive studies.

Late in 1995 and early 1996, 4 epidemiologic studies were published that resulted in a crude mean weighted relative risk of approximately 2 when third-generation oral contraceptives were compared with second-generation oral contraceptives as risk factors for venous thromboembolism. This article reviews empirical evidence on bias or systematic error that may have influenced the estimates of association. The Bradford-Hill criteria to distinguish causality from an observed association were used to consider whether third-generation oral contraceptives cause an apparent excess in the occurrence of venous thromboembolism. Bias is more likely than a causal relationship to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation oral contraceptives. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation products have not been detected. The clinical importance and the public health significance of any differences among the various products with respect to adverse cardiovascular outcomes are trivial and undetectable because of the extremely low incidence of those disorders among users of oral contraceptives. The oral contraceptive pill is 99.9% effective when used correctly. All oral contraceptives on the market are safe and getting safer.

PIP: Four epidemiologic studies published in 1995-96 reported a crude mean weighted relative risk for venous thromboembolism of approximately 2 when third-generation oral contraceptives (OCs) were compared with second-generation formulations. This paper considers empirical evidence of bias or systematic error that may have influenced the estimates of association. Specifically, it asks 1) whether an odds ratio of 2 for venous thromboembolism in users of third- compared with second-generation OCs is accurate or has been spuriously increased by bias and 2) whether causality can be assumed from the observed association reflected in a relative risk of 2. Bias--particularly healthy user, prescription, and referral bias--is more likely than a causal association to explain the associations observed for venous thromboembolism. For myocardial infarction, bias may mask the full benefit of third-generation OCs. For stroke, the question of causality is moot because statistically significant differences between third- and second-generation OCs have not been detected. Moreover, the clinical importance and public health significance of any differences between these OCs in terms of adverse cardiovascular outcomes are trivial because of the extremely low incidence of these disorders among OC users.

Effects on hemostatic variables of desogestrel- and gestodene-containing oral contraceptives in comparison with levonorgestrel-containing oral contraceptives: a review.

In some studies third-generation oral contraceptives have been reported to be associated with a higher risk of venous thromboembolism than are second-generation oral contraceptives, whereas recent, more refined studies have not confirmed this. The reasons for the alleged differences are under discussion, and differential effects on hemostasis have been proposed. Eighteen studies comparing second- and third-generation oral contraceptives with respect to their effects on hemostasis were analyzed. Significant changes from baseline were reported for many variables with both second- and third-generation oral contraceptives without significant between-group differences. Also, in a combined analysis of nonsignificant changes, no consistent pattern of change emerged for any marker, with the exception of higher factor VII levels associated with third-generation oral contraceptives. However, factor VII is not related to venous thromboembolism risk. In addition, 1 cross-sectional study with an unvalidated assay reported a higher ratio of activated protein C sensitivity with third-generation oral contraceptives. Only 2 components of the hemostatic system (factor VII and activated protein C sensitivity ratio) emerged as potentially differentially affected by second- and third-generation oral contraceptives; the association with venous thromboembolism risk is questionable in the former case and unknown in the latter.

PIP: The initial finding of an increased risk of venous thromboembolism in users of third-generation oral contraceptives (OCs) has not been confirmed in recent, more methodologically refined studies. This article reviews 17 prospective studies with healthy volunteers and one cross-sectional study that compared second- and third-generation OCs in terms of their effects on markers of hemostasis. Significant changes from baseline were reported for many variables with both second- and third-generation OCs. For example, activated partial prothrombin clotting time, protein S, and tissue plasminogen activator and its inhibitor were reduced during OC treatment. However, none of the studies reported statistically significant differences between treatment groups for any of these markers. In a combined analysis of nonsignificant changes, no consistent pattern emerged for any coagulation or fibrinolysis parameter with the exception of higher factor VII levels (not related to venous thromboembolism risk) associated with third-generation formulations. The cross-sectional study with an unvalidated assay found a higher ratio of activated C protein sensitivity with third-generation OCs. Only two components of the hemostatic system--factor VII and activated protein C sensitivity ratio--emerged as potentially differentially affected by second- and third-generation OCs. The association with venous thromboembolism risk is questionable in the former cases and unknown in the latter.

Thrombotic diseases in young women and the influence of oral contraceptives.

OBJECTIVE: In the evaluation of the clinical impact of thrombotic diseases in young women, age-specific incidence rates must be calculated for both arterial and venous thrombotic diseases, but also the case-fatality rate and figures for the clinical consequences among those who survive thrombosis must be included. The aim of this analysis was to quantify the clinical impacts of both arterial and venous thrombotic diseases among young, nonpregnant women and thereafter to assess the influences of oral contraceptives on these measures. STUDY DESIGN: Nationwide register data on the morbidity and mortality of venous thromboembolism, myocardial infarction, and thrombotic stroke in Denmark, 1980-1993, and 3 ongoing case-control studies to assess the influence of oral contraceptives on the risk for development of these thrombotic diseases. RESULTS: In women 15-29 years old venous thromboembolism is about twice as common as arterial complications, whereas in women 30-44 years old the number of arterial complications exceeds that of venous diseases by about 50%. The mortality rate from arterial diseases is 3.5 times higher than that from venous diseases among women <30 years old and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability among women who had an arterial complication was about 30%; the proportion was about 5% among women with venous thromboembolism. CONCLUSION: Anticipating a differential influence on venous and arterial diseases from oral contraceptives with second- and third-generation progestogens, it was calculated that users of oral contraceptives with second-generation progestogens had 30% greater increased risk of thrombotic diseases, 260% greater increased risk of thrombotic deaths, and 220% greater increased risk of thrombotic disability than users of oral contraceptives with third-generation progestogens.

PIP: The influence of oral contraceptive (OC) use in young women on the risk of development of venous thromboembolism, myocardial infarction, and thrombotic stroke was assessed through an analysis of nationwide register data from Denmark for 1980-93 and for 1994-95 from three ongoing case-control studies. All three diseases increased rapidly with increasing age; the arterial diseases increased almost exponentially, while the venous diseases increased more linearly. Venous thromboembolism was almost twice as prevalent as arterial complications in women 15-29 years old, while the number of arterial complications exceeded that of venous diseases by about 50% in women 30-44 years of age. Mortality from arterial diseases was 3.5 times higher than that from venous diseases among women under 30 years of age and 8.5 times higher than that from venous diseases in women 30-44 years old. The proportion of women with a significant disability was about 30% among those with an arterial complication; this proportion was 5% among women with venous thromboembolism. Users of OCs with second-generation progestogens had a 30% greater increased risk of thrombotic diseases, a 260% greater increased risk of thrombotic mortality, and a 220% greater increased risk of thrombotic disability than users of OCs with third-generation progestogens.

Myocardial infarction and stroke in young women: what is the impact of oral contraceptives?

Recent discussions have centered on the small apparent risk increase for venous thromboembolism found with newer oral contraceptives (third-generation oral contraceptives containing the progestins desogestrel and gestodene) compared with older oral contraceptives (second-generation). This article reviews the studies addressing the association between oral contraceptive use and thromboembolic conditions affecting the arterial system, ischemic stroke, and myocardial infarction. Differences are found between a US database study, which showed no risk of ischemic stroke or myocardial infarction associated with low-dose oral contraceptive use, and the European studies, which showed oral contraceptive use in general to be associated with increased risks of ischemic stroke and myocardial infarction. The European studies showed no difference between oral contraceptive generations with respect to the occurrence of ischemic stroke; however, the risk of myocardial infarction associated with oral contraceptive use was consistently lower for third- than for second-generation oral contraceptives. Although there seems to be no differential risk of ischemic stroke associated with oral contraceptive generations, third-generation oral contraceptives appear to be consistently associated with no excess risk of myocardial infarction. In all instances, however, cardiovascular risk factors other than oral contraceptive use play the predominant role in the occurrence of ischemic stroke and myocardial infarction.

PIP: This article reviews seven recent studies that addressed the association between second- and third-generation oral contraceptive (OC) use and the risk of ischemic stroke and/or myocardial infarction. The one US study found no risk of ischemic stroke or myocardial infarction with low-dose OC use, while the European studies detected increased risks of both these events. The European studies showed no difference between OC generations in terms of the occurrence of ischemic stroke; however, the risk of myocardial infarction was consistently lower for third- compared with second-generation OCs. In all instances, cardiovascular risk factors other than OC use, especially smoking and hypertension, play the predominant role in the occurrence of both ischemic stroke and myocardial infarction.

Oral contraceptives and venous thromboembolic disease: the findings from database studies in the United Kingdom and Germany.

OBJECTIVE: Three research articles published in late 1995 and early 1996 suggested that oral contraceptives containing either of the newer progestogens (gestodene or desogestrel) could be associated with an increased risk of venous thromboembolism. During the months after the initial publications, the results have been scrutinized with great care and further studies have been published. The findings of 2 recent database studies, 1 in the United Kingdom and 1 in Germany, are presented in this article. PATTERNS OF USE: The average age of users of combined oral contraceptives in Germany was 27 years, compared with 26 years in the United Kingdom. In Germany the use of gestodene-based products was lower than that in the United Kingdom. In the United Kingdom the users of desogestrel with 20 microg ethinyl estradiol (Mercilon) were older than the users of desogestrel with 30 microg ethinyl estradiol (Marvelon). CRUDE INCIDENCE: The crude incidence of venous thromboembolism in the UK study was 4.1 cases/10,000 woman-y exposure to combined oral contraceptives. In Germany it was 4.2 cases/10,000 woman-y. In Germany the rates among users of second-generation combined oral contraceptives were higher than those among users of third-generation products. The reverse was the case in the United Kingdom. In the United Kingdom the crude incidence rates were higher for the 20 microg estrogen desogestrel product than for the 30 microg product. CASE-CONTROL ANALYSIS: The adjusted odds ratios in the UK study did not show significant increases for desogestrel or gestodene compared with levonorgestrel products. There were inconsistencies in the results among centers in the 2 international studies (the World Health Organization and Transnational studies). In both there was a consistent inverse dose-response relationship with estrogen in all centers. CONCLUSION: The limitations of the observational studies are such that the hypothesis that the newer progestogens are more likely to cause venous thromboembolism cannot be proved.

PIP: Research articles published in 1995-96 suggested that oral contraceptives (OCs) containing desogestrel or gestodene are associated with an increased risk of venous thromboembolism. This paper presents the findings of two more recent studies on this association, one from the UK and the other from Germany, both of which were based on general practice computer-generated clinical databases. The median age of OC users was 26 years in the UK study and 27 years in the German study. The crude incidence of venous thromboembolism per 10,000 woman-years of OC exposure was 4.1 cases in the UK study and 4.2 cases in Germany. In Germany, this rate was higher among users of second-generation OCs (4.03 cases per 10,000 woman-years) than third-generation OCs (3.95 cases per 10,000 woman-years). In the UK, the reverse pattern was found: 4.96 and 3.10 cases per 10,000 woman-years for third- and second-generation products, respectively. Moreover, crude incidence rates were higher for the 20 mcg estrogen-desogestrel formulation than for the OC containing desogestrel and 30 mcg of estrogen--a biologically implausible finding. The adjusted odds ratios in the UK study did not show any significant increases in venous thromboembolism risk for desogestrel or gestodene compared with levonorgestrel. Overall, these findings fail to provide support for the hypothesis that the newer progestogens are more likely to cause venous thromboembolism.

Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis.

OBJECTIVE: The objective of this study is to estimate the risk of subarachnoid hemorrhage produced by oral contraceptive use. METHODS: Studies published since 1960 were identified using MEDLINE, Cumulated Index Medicus, Dissertation Abstracts On-line, and bibliographies of pertinent articles. Two independent reviewers screened published cohort and case-control studies that evaluated the risk of subarachnoid hemorrhage associated with oral contraceptives. Eleven of 21 pertinent studies met predefined quality criteria for inclusion in the meta-analysis. Relative risk (RR) estimations evaluating subarachnoid hemorrhage risk in oral contraceptive users compared with nonusers were extracted from each study by two independent reviewers. Study heterogeneity was assessed by design type, outcome measure (mortality versus incidence), exposure measure (current versus ever use), prevailing estrogen dose used, and control for smoking and hypertension. RESULTS: The overall summary RR of subarachnoid hemorrhage due to oral contraceptive use was 1.42 (95% CI, 1.12 to 1.80; p = 0.004). When the two study results failing to control for smoking were excluded from the analysis, a slightly greater effect was seen, with an RR of 1.55 (95% CI, 1.26 to 1.91; p < 0.0001). In the six studies controlling for smoking and hypertension the RR was 1.49 (95% CI, 1.20 to 1.85; p = 0.0003). High-estrogen oral contraceptives appeared to impart a greater risk than low-dose preparations in studies controlling for smoking, but the difference was not significant (high-dose RR, 1.94; 95% CI, 1.06 to 3.56; low-dose RR, 1.51; 95% CI, 1.18 to 1.92). CONCLUSIONS: This meta-analysis of observational studies suggests that oral contraceptive use produces a small increase in the risk of subarachnoid hemorrhage.

PIP: Both case-control and cohort studies have evaluated the risk of subarachnoid hemorrhage (SAH) among oral contraceptive (OC) users and identified relative risks as low as 0.5 and as high as 6.5. To determine whether OC use is indeed a risk factor for SAH after accounting for the variability in study designs and results, a meta-analysis was conducted of the 11 salient independent studies included in the research literature. The summary estimate of effect for all studies was a relative risk (RR) of 1.42 (95% confidence interval (CI), 1.12-1.80). There was a trend toward smaller RRs in the most recent studies, presumably as a result of decreases in the estrogen dose of modern OCs. In the 6 studies that controlled for both smoking and hypertension, the summary RR was 1.49 (95% CI, 1.20-1.85). Only 2 of the 11 studies found a protective effect of current OC use on SAH risk, and it was nonsignificant. Taken together, these studies support a weak positive association between OC use and SAH risk. In the US, an additional 430 patients each year with OC-related SAH would be expected. For most women, the SAH risk is inconsequential in evaluating the decision about OC use. However, for women at high risk of SAH due to unruptured aneurysms, a strong positive family history, smoking, or hypertension, it may be advisable to consider alternative contraceptive methods until more data are available.

Impact of the October 1995 pill scare in Grampian.

Over two years have elapsed since the Department of Health issued a press release concerning the safety of some third generation contraceptive pills. Warnings about increased abortion rates followed and recently published national figures for England and Wales have confirmed this. In Grampian we have assessed the impact of the pill scare at a subnational level, which has received much less consideration. Grampian has a stable population with an estimated 116,500 women in the reproductive years. The six month period from November 1995 until April 1996 was chosen to monitor the immediate aftermath of the pill scare. Aberdeen Royal Infirmary provides a regional, dedicated abortion service and has maintained a service specific database since 1994. This is an ideal situation to monitor trends in abortion rates in a specific population. Women attending for abortion counselling were asked to complete a questionnaire regarding their recall of media publicity. Live-births at Aberdeen Maternity Hospital from June to November 1996 were also recorded, reflecting conceptions in the study period. Prescribing patterns for combined pills and emergency contraception for Grampian general practitioners and Grampian Healthcare family planning service were also analysed. There was no increase in the abortion rate in the study period when compared with the same period in the preceding year - a total of 728 women underwent an abortion. Forty six women were identified within the 728 as having conceived as a direct consequence of the scare, but their characteristics were not dissimilar to the other women on the database. Live-birth rates were also stable. Emergency contraception prescribing was slightly increased for the family planning service but not in general practice. Both general practice and the family planning service showed an immediate and sharp fall in prescribing of third generation pills mirrored by an increase in second generation pill prescribing. For family planning particularly, prescriptions for third generation pills have shown an increase again from early 1996, although remaining below original levels. Fifty five per cent of the women who were given the questionnaire about media publicity responded. Seventy nine per cent recalled some publicity, but 17 per cent of these women could not remember any specific details. Unlike national reporting, our figures do not substantiate any increase in abortions or deliveries in the aftermath of the pill scare. The slight increase in emergency contraception prescribing by the family planning service more probably reflects local awareness campaigns rather than any appreciable switch away from regular pill use. On a population level, the scare did not have the predicted negative impact on pill users in Grampian and it would have been incorrect for us to extrapolate from national data in this instance. Failure to demonstrate numerical impact for the population does not deny the devastating effect of a termination for an individual woman. The emotional impact of the scare on women, while more difficult to measure, should not be underestimated. The influence on the next generation of women with regard to their contraceptive choice remains to be seen.

PIP: The effect of the October 1995 "pill scare" on induced abortion rates has been investigated for England and Wales, but little consideration has been given to the impact at the subnational level. The present study used data from Aberdeen (Scotland) Royal Infirmary from November 1995 to April 1996 to monitor abortion rate trends in the immediate aftermath of negative publicity about the pill's side effects among the estimated 116,500 Grampian women of reproductive age. There were 728 pregnancy terminations in the study period compared with 723 in the same months in the preceding year. 46 of the 728 women who aborted claimed they conceived as a result of media publicity about the pill's side effects (e.g., discontinued all contraceptive use or switched to condoms or a lower-dose pill); they did not differ significantly from the other women undergoing abortion in terms of age, parity, or number of previous terminations. Moreover, the proportion of induced abortions resulting from failure to use effective, reliable contraception remained constant at 80% both before and after the pill scare. A separate analysis of prescribing patterns of Grampian general practitioners and family planning services revealed an immediate, sharp fall in prescribing of third-generation pills and concomitant increases in second-generation pill prescribing. The number of third-generation pills prescribed began to rise again in early 1996, without reaching previous levels. Finally, of the 403 abortion patients who responded to a postal questionnaire, 319 (79%) recalled some publicity about the pill, but 17% could not remember any of the details. Although these findings fail to substantiate an increase in abortions after the October 1996 publicity, the emotional impact of the scare on individual women and its influence on the contraceptive choices of the next generation should not be dismissed.

Resistance to activated protein C, highly prevalent amongst users of oral contraceptives with venous thromboembolism.

OBJECTIVE: Inherited resistance to activated protein C (APC resistance), which is caused by a single point mutation in the factor V gene, is a frequent risk factor for venous thromboembolism. The aim of this study was to determine the prevalence of APC resistance and other coagulation disorders in fertile women with venous thromboembolism and also the risk factors these women had been exposed to in connection with thromboembolic events. DESIGN: A retrospective, case-control study of 36 month duration. SETTING: The study was carried out at Blekinge Hospital, Karlskrona, Sweden. SUBJECTS: The study population comprised 27 fertile women age 16-47 years with thromboembolic complications, referred to the department of Internal Medicine at Blekinge Hospital in Karlskrona during a 36-month period. RESULTS: APC resistance was found in 10 out of 27 women. APC resistance was associated with treatment with oral contraceptives in five out of six women and with pregnancy in one of seven women. All women with resistance to APC developed venous thrombosis in association with a predisposing situation (risk situation) such as surgery, trauma, immobilization, pregnancy, inflammatory state or the use of oral contraceptives. Amongst women not resistant to APC, all but one developed thrombosis in connection with a risk situation. CONCLUSION: APC resistance was found to be highly prevalent amongst fertile women with a history of thromboembolic complication occurring during their use of oral contraceptives.

PIP: Resistance to activated protein C (APC), caused by a single point mutation in the factor V gene, is a significant risk factor for venous thromboembolism. Studies conducted in Sweden have found prevalences of APC resistance ranging from 7% to 15%. The prevalence of this and other risk factors was investigated retrospectively in 27 fertile women 16-47 years of age admitted to Blekinge Hospital (Karlskrona, Sweden) with venous thromboembolism during a 36-month period (1992-94). APC resistance was detected in 10 (37%) of these women, 7 of whom had a family history of venous thrombosis. All 10 women with APC resistance had been exposed to at least one other risk factor. Oral contraceptive (OC) use was reported by 5 women in the APC resistance group and by 1 non-APC resistant case; 5 of these OC users took a pill containing desogestrel. 7 women with venous thromboembolism (1 in the APC-resistant group) were pregnant or postpartum. Other risk factors included surgery (n = 5) and pregnancy-related immobilization (n = 4).

Influence of hormonal contraceptives on microbial flora of gingival sulcus.

To determine a possible influence of two different hormonal contraceptives on bacterial microflora of gingival sulcus, subgingival plaque samples of 29 healthy women aged between 20 and 32 years were investigated bacteriologically before subjects took a contraceptive and 10 and 20 days after subjects started the medication. In 14 women, and oral contraceptive containing 0.02 mg ethinyl estradiol and 0.15 mg desogestrel (preparation A) was used, and 15 women took a contraceptive containing 0.03 mg ethinyl estradiol and 2.00 mg dienogest (preparation B) daily over 21 days. There were no changes in clinical parameters of the teeth investigated during 3 weeks of the study. The periodontopathogenic bacteria Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were never detected throughout the study. On the other hand, the periodontopathogenic species Prevotella intermedia was found in plaque samples of 22 women. The content of this microorganism showed only a little change between the pretreatment period and plaque sampling after 10 days of contraceptive treatment, but a striking increase occurred after 20 days of contraceptive treatment, especially in the preparation A group. In this respect, there was a significant difference between preparations A and B.

PIP: Several studies have suggested an association between sex hormones and chronic inflammatory periodontal disease. This study investigated the impact of two oral contraceptives (OCs) on bacterial microflora of gingival sulcus samples obtained from 29 women 20-32 years of age recruited from Jena (Germany) University Women's Hospital. Study participants were randomly assigned to receive an OC containing either 0.02 mg of ethinyl estradiol and 0.15 mg of desogestrel (n = 14) or 0.03 mg of ethinyl estradiol and 2.00 mg of dienogest (n = 15). Subgingival plaque samples were obtained before and 10 and 20 days after the initiation of OC use. No changes in clinical parameters of the upper incisors (i.e., bleeding on probing, pocket depth, plaque) occurred in either study group during 21 days of OC use. Although Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans were not detected, 22 plaque samples showed evidence of the periodontopathogenic bacteria Prevotella intermedia. The mean cultivable content of this microorganism increased significantly in users of the OC containing desogestrel from 1.2% at day 10 of OC use to 10.0% at day 20, but decreased slightly in women assigned to the OC containing dienogest and a higher dose of ethinyl estradiol. Good oral hygiene is essential in pregnancy and during OC use to compensate for hormonal influences and prevent gingivitis.