Generation Oral Contraceptives Research Articles

Combined oral contraceptives, smoking, and cardiovascular risk.

STUDY OBJECTIVE: To assess age specific incidence and mortality of stroke, acute myocardial infarction (AMI), and idiopathic venous thromboembolism (VTE) associated with use of modern low dose combined oral contraceptives...

Cerebral Thrombosis and Oral Contraceptives

To assess the influence of oral contraceptives (OC) on the risk of cerebral thrombosis and transient cerebral ischemic attacks, a 5-year case-control study including all Danish hospitals was conducted. All women 15-44 years old who suffered a cerebral thromboembolic attack (CTA) during the period 1994-95 and 1200 age matched control subjects were included. Of 309 patients and 1200 control subjects questionnaires sent out, 271 patients (87.7%) and 1074 control subjects (89.5%) responded and agreed to participate. After exclusion of women with nonvalid diagnoses, previous thromboembolic diseases, or current pregnancy, 219 patients and 1041 control subjects were available for analysis. After confounder control and with nonusers as reference, current users of first generation OC (50 micrograms of ethinyl estradiol [EE] or estrans) had an odds ratio (OR) of CTA of 1.86 (95% confidence interval [CI] 0.88-3.92); users of second generation OC (levonorgestrel or norgestimate) had an OR of 2.37 (1.35-4.16); and users of third generation OC (desogestrel or gestodene) had an OR of 1.32 (0.78-2.22). Users of OC with 50, 30-40, or 20 micrograms EE had OR of 2.65 (1.11-6.34), 1.60 (1.05-2.43), and 1.59 (0.57-4.58), respectively. Odds ratios for specific progestin types were as follows: estrans 1.37 (0.60-3.13), levonorgestrel 2.43 (1.40-4.21), norgestimate 7.09 (1.87-26.8), desogestrel 1.62 (0.72-3.63), and gestodene 1.24 (0.67-2.30). Duration of use was without significant influence on the risk and the OR were constant across the age bands. Compared with women who had never used OC, former users had an OR of CTA of 0.95 (0.66-1.51). In conclusion, use of OC with 50 micrograms of EE and OC with second generation progestins increased the risk of CTA significantly. OC with third generation progestins did not have any significant influence on the risk of CTA. The risk of CTA among former users of OC was not increased.

Effect of oral contraceptive progestins on serum copper concentration.

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. Cross-sectional epidemiologic study. Examinations included a detailed questionnaire on medical history and lifestyle factors, a seven day food record, and blood samples. National health and nutrition survey among healthy people living in private homes in West Germany in 1987-1988. Nonpregnant and nonlactating women aged 18-44 y (n = 610). 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%). 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.

Cerebral thrombosis and oral contraceptives: A case-control study

To assess the influence of oral contraceptives (OC) on the risk of cerebral thrombosis and transient cerebral ischemic attacks, a 5-year case-control study including all Danish hospitals was conducted. All women 15–44 years old who suffered a cerebral thromboembolic attack (CTA) during the period 1994–95 and 1200 age matched control subjects were included. Of 309 patient and 1200 control subjects questionnaires sent out, 271 patients (87.7%) and 1074 control subjects (89.5%) responded and agreed to participate. After exclusion of women with nonvalid diagnoses, previous thromboembolic diseases, or current pregnancy, 219 patients and 1041 control subjects were available for analysis. After confounder control and with nonusers as reference, current users of first generation OC (50 μg of ethinyl estradiol [EE] or estrans) had an odds ratio (OR) of CTA of 1.86 (95% confidence interval [CI] 0.88–3.92); users of second generation OC (levonorgestrel or norgestimate) had an OR of 2.37 (1.35–4.16); and users of third generation OC (desogestrel or gestodene) had an OR of 1.32 (0.78–2.22). Users of OC with 50, 30–40, or 20 μg EE had OR of 2.65 (1.11–6.34), 1.60 (1.05–2.43), and 1.59 (0.57–4.58), respectively. Odds ratios for specific progestin types were as follows: estrans 1.37 (0.60–3.13), levonorgestrel 2.43 (1.40–4.21), norgestimate 7.09 (1.87–26.8), desogestrel 1.62 (0.72–3.63), and gestodene 1.24 (0.67–2.30). Duration of use was without significant influence on the risk and the OR were constant across the age bands. Compared with women who had never used OC, former users had an OR of CTA of 0.95 (0.66–1.51). In conclusion, use of OC with 50 μg of EE and OC with second generation progestins increased the risk of CTA significantly. OC with third generation progestins did not have any significant influence on the risk of CTA. The risk of CTA among former users of OC was not increased.

Abstracts of Literature

Abstracts of Literature

The pill and venous thromboembolism: a disarray of several layers of debate.

In the transient period that we are waiting for the full report of the independent Scientific Group Meeting on Cardiovascular Disease and Steroid Hormone Contraceptives [World Health Organization (WHO), 1997], many are anxious to present their view on the third generation oral contraceptives debate. In the overwhelming publication waves so far, different layers of debate can be distinguished, which may hamper a balanced view on the subject. The issues in the scientific debate are clear. Since 1961, the history of oral contraceptives and venous thromboembolism (VTE) has known of several acmes: involvement of a oestrogens in the development of VTE, the interaction between an inheritable coagulation disorder (Factor V Leiden) and oral contraceptive use, and the recent Unding that gestagens are also engaged in the ontogenesis of VTE. Although the last observation has been criticized some epidemiologists are carrying the criticism so far as to jeopardize the core of their own profession's knowledge the independent WHO Scientific Committee, having the disposal of all available Information, confirmed its existence as demonstrated in the four original studies (WHO, 1995, Jick et αϊ, 1995; Bloemenkamp et αϊ, Spitzer et αϊ, 1996). While a biological explanation of the phenomenon that steroids may evoke a process leading to VTE has been lacking since the early 1960s, the epidemiological findings of the 1990s have opened the way towards a beginning of a mechanistic explanation. Resistance to activated protein C (APC) as an effect of oral contraceptives, also reported in the original lest for APC resistance (0sterud et αϊ, 1994; Meinardi et αϊ, 1997; Lowe et αϊ, 1997) is an encouraging first step in our understanding. Despite the thrilling scientific progress on this matter, the finding that some gestagens carry more of an extra risk of VTE than others, leads to debates on the prescription of oral contraceptives a Situation we experienced earlier with the increased risk of VTE in women using high-dose oestrogens and more recently with carriers of Factor V Leiden (Vandenbroucke et αϊ, 1996). Some commentators are minimizing the risk of VTE in oral contraceptive users by admonishing the public that the absolute risk is negligible. Claiming that 'two times a low absolute risk of VTE remains a low absolute risk' is a reaction that does not consider the existence of highly effective alternatives for third generation pills. In younger women, VTE rather than myocardial infarcVenous thromboembolism and the pill

Oral contraceptive use before and after the latest pill scare in the Netherlands: Changes in oral contraceptive use and how users change

In October 1995, a “pill scare” developed in Europe. In the Netherlands, the recommendations given were 1) to not alarm women without risk for deep vein thrombosis (DVT), and 2) to be reserved in prescribing third generation oral contraceptives (OC) for young women who were beginning OC use. To determine whether there is a change in the prescription of third generation OC after the latest pill scare, prescription data from 1/10/94 to 1/10/96, covering a population of ±120,000 persons, were studied with respect to OC use before and after the pill scare. Trend analyses revealed a significant decline in third generation compared with total OC prescribing only in the youngest age category (p = 0.0034). Further, switch behavior was studied. Switches from third to second generation OC were more prevalent after the pill scare than before (odds ratio = 2.63; 95% confidence interval 1.84–3.75) and switches from second to third generation OC were significantly less prevalent after the pill scare. This indicates that Dutch prescribers have reacted to the pill scare in the way that the government recommended.

The Risks of Venous Thromboembolic Disease Among German Women Using Oral Contraceptives: A Database Study

This study investigated the risk of venous thromboembolic disease (VTE) between second and third generation combined oral contraceptives, using the German MediPlus database of patient records. Women studied included 42 patients between the ages of 18 and 49 years, with a diagnosis of VTE treated with an anticoagulant, who were exposed to an oral contraceptive (OC). Four controls per patient (168), matched by year of birth and exposure to an OC on the event day, were identified. More women were users of second generation than third generation OC, and none were using progestogen-only pills. There was no significant difference between patients and control subjects with respect to the type of OC used on the event day (unadjusted odds ratio for third versus second generation users was 0.77; 95% confidence interval [CI] 0.38–1.57) There was no significant age difference between second and third generation users among patients or control subjects. Between January 1 and the event date, there was no significant difference between the patients and control subjects in terms of the number of oral contraceptive prescriptions, number of consultations for psychotherapeutic complaints, or mixed physical and psychotherapeutic consultations; however, patients did demonstrate significantly more consultations for purely physical complaints compared with control subjects (p <0.0001). There were no significant consultation differences between patients with pulmonary emboli (n = 6) and other VTE patients (n = 36). No significant differences with respect to VTE risk between users of second and third generation oral contraceptives were found in this study. Consultations (physical) for patients were higher than for control subjects before the VTE event. If consultation rate relates to the general health status of a person, this might indicate that VTE risk is higher among women of poorer health, but that this is not related to the type of progestogen in the oral contraceptive that they use.

The role of prescribing and referral bias in studies of the association between third generation oral contraceptives and increased risk of thromboembolism.

Recently published papers have shown a slightly increased risk for venous thromboembolism (VTE) among users of third generation oral contraceptive pills (OC) as compared with users of second generation OC. The extra risk is small (about twofold) and could be explained possibly by biases introduced into the original case-control studies. This paper examines the possible role of prescribing bias (i.e. that doctors would prescribe third generation OC preferentially to women whom they knew to be at risk of VTE) and referral bias (i.e. that doctors would preferentially refer women on third generation OC to hospital for investigations of symptoms suggestive of VTE). A cross-sectional survey was carried out of 106 physicians, to record their attitude to the prescription of OC in certain risk situations. Each doctor then extracted data on OC prescription from approximately 12 patients under his care. A total of 1192 patients were included. Data collected related to known risk factors to which the patient was prone, and the type of OC that the woman was taking. The results from the doctors' attitudinal survey showed that third generation oral contraceptives seemed to be very popular among doctors in England and that they would prefer to prescribe third generation to second generation oral contraceptives in virtually all risk situations, and also in situations where there was no particular risk of VTE. The results from the patients' survey, however, did not correspond with the attitudinal survey, and there was no evidence of a systematic bias running through this sample of patients, associating third generation OC prescription with particular risk factors. The results from the doctors' attitudinal survey on referral did not show any evidence of potential bias towards referring patients on third generation OC to hospitals. Comparison of this survey with an equivalent survey done in Germany suggests that there may be different factors governing doctors' behaviour in Germany and England, with reference to choice of OC prescription.

Third Generation Oral Contraceptives and Heritable Thrombophilia as Risk Factors of Non-fatal Venous Thromboembolism

Third generation oral contraceptives (OCs) are apparently stronger risk factors for venous thromboembolism (VTE) than other OCs, however, the increased risk may be due to confounding by indication related to differences in prescription behaviour. We estimated the risk of VTE associated with use of OCs with and without the presence of Factor V Leiden mutation, protein C-, protein S- or antithrombin deficiency. Sixty-seven cases with VTE were compared with 134 controls. The risk of VTE in the presence of thrombophilia was of the same magnitude for third generation OC users as for users of other OCs; OR: 52.5 (95% CI: 3.7-738.1) and OR: 63.3 (95% CI: 6.2-648.4), respectively. It is unlikely that confounding by indication entirely explains the risk of VTE associated with third generation OCs since the combined effect exceeds what could be explained if this source of error was the only determinant of the association.

The role of prescribing and referral bias in studies of the association between third generation oral contraceptives and increased risk of thromboembolism

The role of prescribing and referral bias in studies of the association between third generation oral contraceptives and increased risk of thromboembolism

Thromboembolic Stroke in Young Women: A European Case-Control Study on Oral Contraceptives

A matched case-control study was performed between 1993 and 1996 in 16 centers in the United Kingdom, Germany, France, Switzerland, and Austria. The objective was to determine the influence of oral contraceptives (OC), particularly those containing modern progestins, on the risk for ischemic stroke in women aged 16–44 years. A total of 220 women who had had an incident ischemic stroke and were compared with 775 control subjects who were unaffected by stroke. At least one hospital and one community control subject per patient was matched and interviewed with the corresponding patient for 5-year age band and for area of residence. Crude odds ratios (95% confidence intervals [CI]) for ischemic stroke were as follows. For current use of any OC versus no use 2.3 (1.7–3.2), the adjusted odds ratio (OR) 3.6 (2.4–5.4). The OC associated risk was higher for first generation than for second or third generation OC. The risk estimates for patients versus community control subjects were always lower than for hospital control subjects. No major regional difference of the risk estimates was found. Compared with nonusers of OC without hypertension, women with hypertension who used OC had an almost 10-fold increased risk. However, OC users who had had a blood pressure check before OC prescription had a lower risk than did those without such a check. Smoking >10 cigarettes/day is associated with higher risk of stroke, particularly for OC users. No significant effect was found for duration of OC use. We conclude that although there is a small relative risk of occlusive stroke for healthy women currently using OC, the attributable risk is very small because the incidence in this age group is very low. The small increase in risk of OC use may be further reduced by preventive efforts for cardiovascular risk factors, particularly hypertension and smoking.

Case-control study of oral contraceptives and risk of thromboembolic stroke: results from international study on oral contraceptives and health of young women

Objective: To determine the influence of oral contraceptives (particularly those containing modern progestins) on the risk for ischaemic stroke in women aged 16–44 years.Design: Matched case-control study.Setting: 16 centres in...

Mortality from venous thromboembolism among young women in Europe: no evidence for any effect of third generation oral contraceptives.

STUDY OBJECTIVE: To investigate whether there has been an increase of venous thromboembolism (VTE) mortality in European countries, concurrent with the replacement of second generation by third generation combined oral...

The 1995 pill scare revisited: anatomy of a non-epidemic.

Two years after the October 1995 pill scare that received worldwide attention, this synthesis of evidence goes back to the earliest research on risks of first generation oral contraceptives (OCs). It also covers epidemiological data published since, emphasising the 1995-1996 findings. Late breaking data are also examined. The key issue: are there differences in the risk profiles of second and third generation OCs. The ultimate question is: did any epidemics of venous thromboembolism (VTE) occur? This synthesis of evidence leads to the following conclusions and observations: (i) all OCs on the market are becoming progressively safer; (ii) relative risks of about 2 for VTE, even if real, are clinically unimportant and of no public health significance; (iii) the weak odds ratios contrasting third and second generation OCs, ranging from 1.5 to 2.3 in the 1995-1996 studies are more likely explained by bias than by a causal relationship; (iv) incidences of VTE among users of any OC have been declining over the past three decades; (v) absolute rates of VTE for third generation OC users reported in 1995-1996 are lower than those for users of second generation OCs in 1988 and 1991; (vi) there is no difference in risk of VTE between first starters on second generation OCs versus first starters on third generation OCs; (vii) users of third generation OCs are at much lower risk of acute myocardial infarction than users of second generation OCs; (viii) among users of any OC, the occurrence rates of stroke are low, they are declining, and no differences between second and third generation OCs are apparent; (ix) 2 years after the pill scare there are no epidemics of VTE; (x) there have been excessive rates of therapeutic abortions in some countries; and (xi) the benefit-risk ratio is favourable for users of any OC.

Third generation oral contraceptives and risk of myocardial infarction: An international case-control study: Lewis MA, Spitzer WO, Heinemann LA, et al. Br Med J. 1996:312:88–90

Third generation oral contraceptives and risk of myocardial infarction: An international case-control study: Lewis MA, Spitzer WO, Heinemann LA, et al. Br Med J. 1996:312:88–90

The use of oral contraceptives and the occurrence of acute myocardial infarction in young women: Results from the transnational study on oral contraceptives and the health of young women

The objective of this study was to assess the risk of myocardial infarction (MI) associated with the use of new and old combination oral contraceptives (OC). A matched case-control study in 16 centers in Germany, the United Kingdom, France, Austria, and Switzerland explored the association of current use of combination OC with the occurrence of MI. Our subjects were 182 women aged 16–44 years with MI; the controls were 635 women with-out MI (at least one hospital control and one community control per case) matched for 5-year age group and region. The main outcome measures were odds ratios comparing current use of a specific group of OC against current use of other groups or against no current use. The adjusted overall odds ratio (OR; 95% confidence intervals) for MI for second generation OC versus no current use was 2.35 (1.42 to 3.89) and 0.82 (0.29 to 2.31) for third generation OC (low dose ethinyl estradiol, gestodene, and desogestrel). A direct comparison of third generation users with second generation users yielded an OR of 0.28 (0.09 to 0.86). In subgroup analyses, the odds ratio for the UK alone was 1.25 (0.36 to 4.29), while for continental Europe it was 0.10 (0.02 to 0.48). For hospital controls, the risk estimated was 0.98 (0.22 to 4.44), and 0.18 (0.04 to 0.65) for community controls. The independent risk of MI among current smokers adjusted for OC use was 7.21 (4.58 to 11.36). Among users of third generation OC, the OR for current smokers was 3.75 (0.65 to 21.74) and among users of second generation it was 9.50 (2.93 to 30.96). A comparison of OC use in the UK for the time before and after regulatory action was taken in October 1995 shows that the likelihood of a control (last control accrued June 1996) being treated with second generation OC is seven times higher after 1 November 1995 than it was before. Third generation Oc are the first to be associated with no excess risk of MI. A significantly lower risk of MI is found when comparing use of third generation OC with use of second generation OC. There seems to be an impressive amelioration of risk among smokers using newer OC. An impact of regulatory action in the UK was found in the OC use spectrum of controls.

First-time use of newer oral contraceptives and the risk of venous thromboembolism

Recent epidemiologic studies reported that the risk of venous thromboembolism (VTE) was higher with the use of the newer third generation oral contraceptives than with second generation agents. Although the overall findings of these studies are similar, the results, as they relate to patterns and duration of oral contraceptive use particularly among first-time users, are inconsistent. We reanalyzed data from the Transnational case-control study to assess the risk of VTE associated with first-time use of oral contraceptives as a function of its duration of use. Over the period 1993 to 1995, 471 cases of venous thromboembolism were identified in Germany and the United Kingdom. For each case, up to four controls were obtained, for a total of 1772 controls. Data on oral contraceptive use and confounding variables, including data on sociodemographic, lifestyle, medical history, and family history of disease, were obtained by interview. Data analysis was based on the 105 cases and 422 controls who were first-time users of second or third generation agents, or never users of oral contraception. Rate ratios, adjusted for confounders and approximated by odds ratios, were estimated as a continuous function of duration of oral contraceptive use by logistic regression and quadratic spline models. We found, for first-time users, that the adjusted rate tatio of VTE as a function of the duration of oral contraceptive use is essentially identical for second and third generation pills relative to never users. This rate ratio increases to around 10 in the first year of use and decreases to around two after 2 years of use, remaining at this risk level thereafter for both second and third generation agents. We conclude that second and third generation agents are associated with identical risks of venous thromboembolism when they are prescribed to women who are using oral contraceptives for the first time ever.

Myocardial infarction and oral contraceptives, a retrospective case control study in England and Scotland ('MICA' Study).

Recent studies have shown that modern (third generation), oral contraceptives (OC) are associated with an increased incidence of venous thromboembolic disease compared to older (second generation), OC. It is not known, however, whether this association is also true for arterial thrombosis, in particular myocardial infarction. In fact, it has been suggested that third generation OC may even be protective against myocardial infarction (MI), compared to second generation OC. The protocol for a multicentre case-control study, involving the whole of England and Scotland, is described. Cases will be female patients aged 16-44 years, who suffered an MI between 1.10.93 and 1.10.95. Controls will be drawn from the community, using the GP list, to which the case belonged. Odds ratios will be calculated primarily to compare current users of third generation OC with current users of second generation OC.

Modeled estimates of myocardial infarction and venous thromboembolic disease in users of second and third generation oral contraceptives

Consistent reports from several recent studies suggest that users of third generation oral contraceptives (OCs) containing gestodene and desogestrel may be at increased risk of venous thromboembolic disease (VTE). Paradoxically, other reports indicate that these users may be at decreased risk of acute myocardial infarction (MI) compared with users of second generation OCs. To determine whether the potentially increased risk of VTE would outweigh the potentially reduced risk of MI in users of third generation OCs, we conducted an analysis to quantify the trade-offs providers and users may be faced to make between these formulations. The baseline rates of VTE and MI among non-users were calculated using US data on incidence and mortality of these conditions and estimates of the proportion of women exposed to these formulations in the US. These were multiplied by relative risks published in recent studies on third generation progestins to produce age- and formulation-specific risks. Results indicate that there would be small differences in disease burden between users of second and third generation OCs under the model assumptions at younger ages. However, among women 35–44 years of age, modeling results indicate that the potentially decreased incidence of MI among users of third generation OCs more than offsets the potentially increased risk of VTE at this age.