Users Of Second-generation Oral Contraceptives Research Articles

Risk of idiopathic cerebral haemorrhage in women on oral contraceptives with differing progestagen components

The risk of idiopathic cerebral haemorrhage in users of third-generation oral contraceptives compared with that of users of second-generation oral contraceptives was evaluated using data from the General Practice Research Database. We found no increased risk for third-generation oral contraceptives, compared with second-generation oral contraceptives.

Risk of venous thromboembolism with third-generation oral contraceptives: A review

Recent data indicate that users of third-generation oral contraceptives, those containing the new progestins desogestrel, gestodene, and norgestimate, have 2 to 3 times the risk of venous thromboembolism faced by users of second-generation oral contraceptives. The risk of development of deep vein thrombosis was also found to be 2 to 5 times greater with a low-estrogen, desogestrel-containing oral contraceptive than with second-generation monophasic and triphasic preparations. Investigators point to an acquired resistance to the anticoagulation effects of activated protein C, the most common cause of hereditary thrombophilia, as a possible mechanism. The American College of Obstetrics and Gynecology’s Committee on Gynecologic Practice reconfirms the increased risk of venous thromboembolism associated with third-generation progestins versus other progestins. Because the third-generation oral contraceptives may have benefit for some patients, however, it defers to the individual clinician’s and patient’s judgment regarding the use of a desogestrel-containing formulation (the only third-generation progestin available in the United States). (Am J Obstet Gynecol 1999;180:S295-301.)

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.

Molecular biology and pathophysiology of APC resistance: current insights and clinical implications.

APC resistance is often associated with the occurrence of a single point mutation in factor V (factor VLeiden) at a predominant cleavage site for the natural anticoagulant, activated protein C (APC). In this article we will discuss the effects of this mutation (Arg506-->Gln) on the down-regulation of factor Va cofactor activity and on thrombin formation by APC in model systems and in plasma. Our studies on the effects of APC on thrombin formation in plasma resulted in the development of a new method for the screening of APC resistance that is based on measurement of the effect of APC on the endogenous thrombin potential (the time integral of thrombin generated in clotting plasma). It appeared that sensitivities for APC determined via this method were considerably affected by the use of oral contraceptives (OC) and that women who use OC become acquired APC resistant. The fact that acquired APC resistance in women who use third-generation OC was more pronounced than in users of second-generation OC may explain the further increased risk for venous thrombosis associated with the use of third-generation OC.

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.

Venous Thromboembolism And `Third-Generation' Pills May Not Be Related

A recently published case-control study conducted in the UK suggests that the association between venous thromboembolism risk and use of third-generation oral contraceptives (OCs) identified in an earlier cohort analysis may be an artifact of age confounding. The investigators used computerized records from 143 general practitioners in the UK to compare the incidence of venous thromboembolism among users of the most common OCs and they performed a case-control study to calculate the odds ratio associated with different types of pills. The final sample included 491908 women born during 1941-81 who contributed 234899 woman-years of exposure to steroidal contraception including 108824 woman-years of exposure to third-generation progestogens. In all 85 women had a history of venous thromboembolism (29 users of second-generation OCs 54 users of third-generation products and 2 users of progestin-only pills). After adjustment for 5-year age groups users of third-generation pills were 1.7 times more likely than users of second-generation OCs to have experienced venous thromboembolism a finding consistent with the results of previous studies. The case-control portion of the study compared the 83 women who had a venous thromboembolism with 313 controls matched by physicians practice current OC use and exact year of birth. Regression analyses adjusted for potentially confounding variables revealed no significant differences in venous thromboembolism risk between users of second- versus first-generation OCs. The investigators contend that matching by exact age not 5-year age bands is essential to ensure that controls are representative of the population from which cases are drawn.

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.

New Study Casts Doubt on the Association Between Third-Generation Pills and Venous Thromboembolism

A recent case-control study from the UK raises doubts about the previously noted association between venous thromboembolism and use of third-generation oral contraceptives (OCs) containing the progestins gestodene and desogestrel. The computer records of 143 general practitioners in the UK yielded data on 540000 women born from 1941 to 1981. This sample included 491908 women with 234899 woman-years of exposure to steroidal contraception including 108824 woman-years of exposure to third-generation OCs. 85 women had a venous thromboembolism (29 users of second-generation OCs 54 users of third-generation pills and 2 users of progestin-only pills). The crude rates of venous thromboembolism were 4.1/10000 woman-years of exposure among all combined OC users 3.1/10000 for second-generation OCs and 5.0/10000 for third-generation products. After adjustment for 5-year age groups users of third-generation OCs were 1.7 times more likely than second-generation pill users to have experienced this complication. Case-control analysis of the same data set produced substantially different results however. The 85 women with a venous thromboembolism were matched with 313 controls on physicians practice current use of OCs and exact date of birth. After adjustment for body mass index change in type of contraceptive prescribed within 3 months of the event number of cycles prescribed concurrent disease and use of emergency contraception there was no significant difference in risk of venous thromboembolism associated with second- versus third-generation OCs. Exact matching by age appears crucial to ensure that controls are representative of the population from which cases are drawn and to prevent residual confounding by age.

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.

Population-based study of risk of venous thromboembolism associated with various oral contraceptives

Four studies published since December, 1995, reported that the incidence of venous thromboembolism (VTE) was higher in women who used oral contraceptives (OCs) containing the third-generation progestagens gestodene or desogestrel than in users of OCs containing second-generation progestagens. However, confounding and bias in the design of these studies may have affected the findings. The aim of our study was to re-examine the association between risk of VTE and OC use with a different study design and analysis to avoid some of the bias and confounding of the earlier studies. We used computer records of patients from 143 general practices in the UK. The study was based on the medical records of about 540,000 women born between 1941 and 1981. All women who had a recorded diagnosis of deep-vein thrombosis, venous thrombosis not otherwise specified, or pulmonary embolus during the study period, and who had been treated with an anticoagulant were identified as potential cases of VTE. We did a cohort analysis to estimate and compare incidence of VTE in users of the main OC preparations, and a nested case-control study to calculate the odds ratios of VTE associated with use of different types of OC, after adjustment for potential confounding factors. In the case-control study, we matched cases to controls by exact year of birth, practice, and current use of OCs. We used a multiple logistic regression model that included body-mass index, number of cycles, change in type of OC prescribed within 3 months of the event, previous pregnancy, and concurrent disease. 85 women met the inclusion criteria for VTE, two of whom were users of progestagen-only OCs. Of the 83 cases of VTE associated with use of combined OCs, 43 were recorded as deep-vein thrombosis, 35 as pulmonary thrombosis, and five as venous thrombosis not otherwise specified. The crude rate of VTE per 10,000 woman-years was 4.10 in current users of any OC, 3.10 in users of second-generation OCs, and 4.96 in users of third-generation preparations. After adjustment for age, the rate ratio of VTE in users of third-generation relative to second-generation OCs was 1.68 (95% CI 1.04-2.75). Logistic regression showed no significant difference in the risk of VTE between users of third-generation and second-generation OCs. Among users of third-generation progestagens, the risk of VTE was higher in users of desogestrel with 20 g ethinyloestradiol than in users of gestodene or desogestrel with 30 g ethinyloestradiol. With all second-generation OCs as the reference, the odds ratios for VTE were 3.49 (1.21-10.12) for desogestrel plus 20 g ethinyloestradiol and 1.18 (0.66-2.17) for the other third-generation progestagens. The previously reported increase in odds ratio associated with third-generation OCs when compared with second-generation products is likely to have been the result of residual confounding by age. The increased odds ratio associated with products containing 20 micrograms ethinyloestradiol and desogestrel compared with the 30 micrograms product is biologically implausible, and is likely to be the result of preferential prescribing and, thus, confounding.

Oral contraceptive use and venous thromboembolism: a consideration of the impact of bias and confounding factors on epidemiological studies

Recent epidemiological studies have reported an approximately two-fold, significant, increased odds ratio for venous thromboembolism in users of third-generation oral contraceptives (OCs) compared to users of second-generation OCs. However, in each study, this association is of borderline statistical significance, and the studies do not indicate an increase in the absolute risk of venous thromboembolism for users of third-generation OCs compared with the data from prior studies primarily involving second-generation products. The data derived from these recent studies show a lower reported incidence of venous thromboembolism with the use of second-generation OCs over time compared to the prior studies, while the incidence of venous thromboembolism for use of third-generation OCs is approximately equal to that previously reported for second-generation products. Generally, evidence has shown that the risk of venous thromboembolism and the impact on hemostatic parameters are reduced with declining estrogen dose. In addition, there is no evidence of a clinically significant effect of the OC progestogen doses on hemostatic parameters. These inconsistencies point to factors other than a causal relationship to explain the higher risk of venous thromboembolism in users of third-generation OCs. An examination of factors not included in the recent studies has identified at least three potential biases that should be considered: prescription bias, a 'healthy-user' effect and referral bias. Available data on prescription bias come from marketing research surveys, databases of prescribing patterns, epidemiological databases and the recent studies. These data indicate that the recently introduced third-generation OCs have been more extensively used by younger women, for shorter periods of time, and by women with risk factors for venous thromboembolism that have the second-generation OCs. There is also evidence for a healthy-user effect, whereby women who were most susceptible for venous thromboembolism have left the cohort of users of second-generation OCs as a result of a venous thromboembolism during pregnancy or early OC use, and thus were possibly not included in these recent studies. The women remaining in the cohort, who are included in the recent studies, are less susceptible to venous thromboembolic events than are those making up the cohort of women using third-generation OCs. In addition, there are indications that referral bias has occurred because women with risk factors for venous thromboembolism (who disproportionately receive third-generation OCs) are more likely to be referred to a hospital for investigation of possible symptoms of venous thromboembolism, and thus users of third-generation OCs have the potential to be over-represented among cases. These biases act spuriously to increase the observed odds ratio for the first-time occurrence of venous thromboembolism amongst users of third-generation OCs, when compared to users of second-generation OCs. None of the recent epidemiological studies have been able to adjust for the three major biases. These biases are likely to contribute to, or even totally account, for the small increased risk of venous thromboembolism observed for users of third-generation OCs when compared to that for users of second-generation OCs.