Users Of Third-generation Oral Contraceptives Research Articles

Venous thromboembolism and combined oral contraceptives: does the type of progestogen make a difference?

Venous thromboembolism (VTE) is rare in young women but is associated with the use of combined oral contraceptives (OCs). In 1995 and 1996, three studies showed a difference in the risk of VTE with third-generation OCs containing the progestogens, desogestrel or gestodene, compared with earlier formulations. However, the subsequent MediPlus study did not show any difference in the risk of VTE between users of third- and second-generation OCs. To re-examine the risks of VTE with various OCs, a nested case-control study was undertaken using the General Practice Research Database (GPRD). This study identified 293 cases and selected up to four controls matched for year of birth, practice, and event date. Adjustment for confounding variables included: body mass index, smoking, asthma, diastolic blood pressure, and a proxy for recent illness. The new analysis of the GPRD showed that there was no statistically significant difference in the risk of VTE among users of third-generation OCs compared with second-generation OCs containing levonorgestrel 150 μg plus ethinylestradiol 30 μg. Important associations with idiopathic VTE included: age, obesity, smoking, recent concurrent illness, and asthma. Thus, any difference previously noted between OCs containing desogestrel or gestodene and levonorgestrel are likely to be due to the healthy-user effect, prescribing bias and inadequate control of known confounding variables, such as age and obesity.

Recurrent use of newer oral contraceptives and the risk of venous thromboembolism.

The epidemiological studies that assessed the risk of venous thromboembolism (VTE) associated with newer oral contraceptives (OC) did not distinguish between patterns of OC use, namely first-time users, repeaters and switchers. Data from a Transnational case-control study were used to assess the risk of VTE for the latter patterns of use, while accounting for duration of use. Over the period 1993-1996, 551 cases of VTE were identified in Germany and the UK along with 2066 controls. Totals of 128 cases and 650 controls were analysed for repeat use and 135 cases and 622 controls for switching patterns. The adjusted rate ratio of VTE for repeat users of third generation OC was 0.6 (95% CI:0.3-1.2) relative to repeat users of second generation pills, whereas it was 1.3 (95% CI:0.7-2.4) for switchers from second to third generation pills relative to switchers from third to second generation pills. We conclude that second and third generation agents are associated with equivalent risks of VTE when the same agent is used repeatedly after interruption periods or when users are switched between the two generations of pills. These analyses suggest that the higher risk observed for the newer OC in other studies may be the result of inadequate comparisons of pill users with different patterns of pill use.

The changing scene--an unnecessary pill crisis.

A number of case-control studies published in 1995/1996 have shown an apparent increase in the risk of venous thromboembolism (VTE) associated with the use of third-generation oral contraceptives (OC). However, it was discussed very early on that these studies were subject to a number of biases or residual confounding that would have increased the risk estimates for third-generation OC while lowering those for second-generation preparations. Six new studies or analyses were performed trying to take into account many of the methodological problems that were discussed for the initial studies: Two population-based database analyses in the UK and Germany, a new analysis of the General Practice Registry database (GPRD) in the UK, an analysis of a new database of the Transnational study, a re-analysis of the original Transnational study with a new technique, and a population-based study in Denmark. These studies could not confirm a higher VTE risk in users of third-generation OC compared with those using second-generation OC. Data on the risk of arterial thromboembolism (ischaemic stroke and myocardial infarction) show no such difference between generations of OC, with a statistically significant reduction in the risk of acute myocardial infarction from first- to third-generation preparations in one major study. Some of the investigators concluded that there is very likely no increased risk of arterial thromboembolism associated with the use of low-dose oestrogen OC in young women who are properly screened for cardiovascular risk factors or for such conditions. These findings should be taken into account when interpreting the results of studies on the risk of VTE in women taking combined OC.

Benefits and risks of third-generation oral contraceptives.

To evaluate the risks and benefits of third-generation oral contraceptives. A MEDLINE search was done for English language articles published from 1985 through 1998 relating to the side-effect profile of third-generation oral contraceptives or their association with cardiovascular or thromboembolic disease. All articles containing original data were included. The risk of venous thromboembolism appears to be 1.5- to 2.7-fold greater in users of third-generation, compared with second-generation, oral contraceptives. Compared with nonusers, women who use third-generation oral contraceptives may have a 4.8- to 9.4-fold greater risk of venous thromboembolism. Users of third-generation oral contraceptives do not appear to have an increased risk of myocardial infarction compared with nonusers and may have risk of myocardial infarction of 0.26 to 0.7 compared with second-generation users. Whether third-generation oral contraceptives are associated with a decreased stroke risk is still not clear. Although third-generation oral contraceptives most likely increase a user's risk of venous thromboembolism, their improved side-effect profile and their possible decreased association with myocardial infarction and stroke may make them a useful new class of oral contraceptives for most women except those at increased risk of venous thrombosis.

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.)

Oral contraceptives and vascular reactivity of great vessels in women

Blood pressure and great vessel vascular reactivity, evaluated by color Doppler ultrasound, were investigated in users of third-generation oral contraceptives (n = 18) compared to non-users, who were studied either in the follicular (n = 8) or in the luteal (n= 10) phase of the menstrual cycle. Blood pressure measured at rest in the supine position, evaluated both in the follicular phase and in the luteal phase, was similar between oral contraceptive users and non-users. The pulsatility index (an indirect index of resistance to blood flow) of both the internal carotid artery and the axillary artery was similar in control women studied in the follicular phase and in the luteal phase. By contrast, in users of oral contraceptives, pulsatility index values of the internal carotid artery tended to be higher, whilst those of the axillary artery were significantly higher, than those of women in either the follicular phase (p< 0.01) or the luteal phase (p< 0.025). In conclusion, new third-generation oral contraceptives do not have a significant impact on blood pressure control, but still tend to increase vascular resistance to blood flow, particularly in areas more involved in the regulation of blood pressure, for example the axillary artery.

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.

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.

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.

Contraceptive knowledge and attitudes of Austrian adolescents after mass media reports linking third-generation oral contraceptives with an increased risk of venous thromboembolism

We performed a representative survey to determine the level of knowledge of 1,010 Austrian adolescents aged 14 to 24 years about selected facts relating to the recent massive news coverage of the increase in the risk of venous thromboembolism in users of third-generation oral contraceptives and to assess the contraceptive behavior of this population. The overall use rate of oral contraceptives and condoms had increased significantly between 1991 and 1996. Sixty-six percent of the adolescents surveyed stated not having heard or read any media reports on oral contraceptives. Only 8% of those who had knew that most reports focused on the pill as a possible cause of venous thromboembolism, whereas the majority of respondents indicated that the media conveyed doubts regarding the health safety of oral contraceptives in general. Nearly half of adolescents were unable to define what a thrombosis was. Thus, although the mass media play an important role in transmitting medical information, the dissemination of practical, accurate advice on the risks of a drug and competent patient counseling is reserved for the health care professional.

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.

The immediate effects of the pill safety scare on usage of combined oral contraceptives in north east England.

In October 1995 spurred by information from the Committee on Safety of Medicines the UK Department of Health urged physicians to consider switching users of third-generation oral contraceptives (OCs) containing...

End of the line for “third-generation-pill” controversy?

Through modification of an in vitro test for thrombosis formation, a Dutch research group has made three significant findings: 1) third-generation oral contraceptives (OCs) induce a resistance to the blood's natural anticoagulation system of a magnitude close to that induced by a mutation in coagulation factor V Leiden; 2) second-generation OCs show only part of the effect; and 3) in OC users heterozygous for the factor V Leiden mutation, resistance to the blood's natural anticoagulation system is as high as that among homozygotes for the mutation. These findings are consistent with epidemiologic data indicating a 6- to 9-fold increased risk of deep venous thrombosis among users of third-generation OCs compared with non-users. The presence of factor V Leiden raises this risk 30- to 50-fold. Drug regulatory agencies are urged to issue clear prescription guidelines to protect users of third-generation OCs from severe venous thrombosis.

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.

The influence of thrombotic risk factors when oral contraceptives are prescribed a control‐only study

The aim of this study was to assess preferential prescribing of OC according to different thrombotic risk factors. The control group in an ongoing Danish case-control study on stroke and OCs collected in 1994 and 1995 underwent a control-only analysis concerning the occurrence of thrombotic risk factors among users of different types of OC. Specific attention was given to differences between OCs with second and third generation progestagens. The association between specific risk factors and the pill types was assessed crude and after multivariate analysis with confounder control for age and other risk factors, in order to identify risk factors, which after these corrections still had a significant confounding influence on the prescribing of OC. Users of OCs with third generation progestagens had a significantly higher proportion of familial thrombotic disposition (23.1%) than users of OCs with second generation progestagens (7.1%) (p = 0.01). After correction for age and other risk factors this difference was still highly significant (p = 0.002). Among users of third generation pills the proportion of short time users (< 1 year) (22.4%) was significantly higher than the per cent among users of OCs with second generation progestagens (5.5%) (p < 0.001). This difference was still significant after correction for age and other risk factors (p < 0.001). Smoking, years of schooling, migraine, and body mass index did not differ significantly between the two pill groups. In Denmark, women with familial thrombotic disposition are four times more likely being prescribed OCs with third versus second generation progestagens compared with women without such a disposition. At the same time users of OCs with third generation progestagens include significantly more short time users than users of OCs with second generation progestagens. For thrombotic diseases where familial disposition or duration of use of OCs play a role for the pill-associated risk, these differences may significantly influence the thrombotic risk measures in case-control studies and non-randomized cohort studies unless confounder control is conducted for this selection.

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.