Lothar A.J. Heinemann

Third generation oral contraceptives and risk of venous thromboembolic disorders: an international case-control study. Transnational Research Group on Oral Contraceptives and the Health of Young Women.

Abstract Objective: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of venous thromboembolism. Design: Matched case-control study. Setting: 10 centres in Germany and United Kingdom. Subjects: Cases were 471 women aged 16-44 who had a venous thromboembolism. Controls were 1772 women (at least 3 controls per case) unaffected by venous thromboembolism who were matched with corresponding case for age and for hospital or community setting. Main outcome measures: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables. Results: Odds ratios (95% confidence intervals) for venous thromboembolism were: for any oral contraceptives versus no use, 4.0 (3.1 to 5.3); for second generation products (low dose ethinyloestradiol, no gestodene or desogestrel) versus no use, 3.2 (2.3 to 4.3); for third generation products (low dose ethinyloestradiol, gestodene or desogestrel) versus no use, 4.8 (3.4 to 6.7); for third generation products versus second generation products, 1.5 (1.1 to 2.1); for products containing gestodene versus second generation products, 1.5 (1.0 to 2.2); and for products containing desogestrel versus second generation products, 1.5 (1.1 to 2.2). Probability of death due to venous thromboembolism for women using third generation products is about 20 per million users per year, for women using second generation products it is about 14 per million users per year, and for non-users it is five per million per year. Conclusions: Risk of venous thromboembolism was slightly increased in users of third generation oral contraceptives compared with users of second generation products. Key messages Key messages This case-control study examined risk of venous thromboembolism associated with different types of oral contraceptive Overall, there was a fourfold higher relative risk of thromboembolism associated with current use of any oral contraceptive versus no current use The risk of thromboembolism was 1.5 times higher for third generation contraceptives compared with second generation products Our data indicate the need for clinical prudence but allow doctors and women seeking contraception to exercise informed choice

The Menopause Rating Scale (MRS) scale: a methodological review.

AbstractBackgroundThis paper compiles data from different sources to get a first comprehensive picture of psychometric and other methodological characteristics of the Menopause Rating Scale (MRS) scale. The scale was designed and standardized as a self-administered scale to (a) to assess symptoms/complaints of aging women under different conditions, (b) to evaluate the severity of symptoms over time, and (c) to measure changes pre- and postmenopause replacement therapy. The scale became widespread used (available in 10 languages).MethodA large multinational survey (9 countries in 4 continents) from 2001/ 2002 is the basis for in depth analyses on reliability and validity of the MRS. Additional small convenience samples were used to get first impressions about test-retest reliability. The data were centrally analyzed. Data from a postmarketing HRT study were used to estimate discriminative validity.ResultsReliability measures (consistency and test-retest stability) were found to be good across countries, although the sample size for test-retest reliability was small. Validity: The internal structure of the MRS across countries was astonishingly similar to conclude that the scale really measures the same phenomenon in symptomatic women. The sub-scores and total score correlations were high (0.7–0.9) but lower among the sub-scales (0.5–0.7). This however suggests that the subscales are not fully independent.Norm values from different populations were presented showing that a direct comparison between Europe and North America is possible, but caution recommended with comparisons of data from Latin America and Indonesia. But this will not affect intra-individual comparisons within clinical trials.The comparison with the Kupperman Index showed sufficiently good correlations, illustrating an adept criterion-oriented validity. The same is true for the comparison with the generic quality-of-life scale SF-36 where also a sufficiently close association has been shown.ConclusionThe currently available methodological evidence points towards a high quality of the MRS scale to measure and to compare HRQoL of aging women in different regions and over time, it suggests a high reliability and high validity as far as the process of construct validation could be completed yet.

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 ratio 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.

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 without 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.

Third generation oral contraceptives and risk of myocardial infarction: an international case-control study.

Abstract Objective: To test whether use of combined oral contraceptives containing third generation progestogens is associated with altered risk of myocardial infarction. Design: Matched case-control study. Setting: 16 centres in Austria, France, Germany, Switzerland, and the United Kingdom. Subjects: Cases were 153 women aged 16-44 with a myocardial infarction event. Controls were 498 women (at least 3 controls per case) unaffected by myocardial infarction who were matched with their corresponding case for age and for hospital or community setting within four months of the index infarction. Main outcome measures: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding variables. Results: The estimated odds ratio for myocardial infarction of third compared with second generation oral contraceptives among all 651 study subjects was 0.36 (95% confidence interval 0.1 to 1.2) (P=0.11). The odds ratio for the United Kingdom and Germany alone was 0.45 (0.1 to 1.8) (P=0.26). Other odds ratios for the five countries were 3.1 (1.5 to 6.3) (P=0.003) for use of second generation products v no current use and 1.1 (0.4 to 3.4) (P=0.9) for use of third generation products v no current use. Among the confounding variables the independent contribution of smoking (for which adjustment was made in the above estimates) proved to be important (10.1 (5.7 to 17.9), P<0.001). Conclusion: An odds ratio of 0.45 with wide confidence intervals shows that third generation oral contraceptives compared with second generation products are associated with a reduced risk of myocardial infarction or with no difference. This finding from an interim analysis should be interpreted with extreme caution. However, the excess risk of venous thromboembolism associated with the use of third generation products may be balanced by the reduced risk of myocardial infarction associated with the same products. Key messages Key messages Compared with the results of British studies published in the 1970s, the risk of myocardial infarction among current users v non-users of second generation oral contraceptives was low The risk of myocardial infarction was appreciably lower among women using third generation products, the risk being comparable to that among women who did not use oral contraception and two to three times lower than that among women using second generation products The results suggest that about 12 fewer deaths from myocardial infarction in England and Wales and 46 fewer in Germany would occur each year if all those taking second generation oral contraceptives started taking third generation products Both the risks and the benefits of oral contraceptives need to be considered in a balanced way so that doctors can give judicious advice and women have informed choice

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

Abstract 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 the United Kingdom, Germany, France, Switzerland, and Austria. Subjects: Cases were 220 women aged 16–44 who had an incident ischaemic stroke. Controls were 775 women (at least one hospital and one community control per case) unaffected by stroke who were matched with the corresponding case for 5 year age band and for hospital or community setting. Information on exposure and confounding variables were collected in a face to face interview. Main outcome measures: Odds ratios derived with stratified analyses and unconditional logistic regression to adjust for potential confounding. Results: Adjusted odds ratios (95% confidence intervals) for ischaemic stroke (unmatched analysis) were 4.4 (2.0 to 9.9), 3.4 (2.1 to 5.5), and 3.9 (2.3 to 6.6) for current use of first, second, and third generation oral contraceptives, respectively. The risk ratio for third versus second generation was 1.1 (0.7 to 2.0) and was similar in the United Kingdom and other European countries. The risk estimates were lower if blood pressure was checked before prescription. Conclusion: Although there is a small relative risk of occlusive stroke for women of reproductive age who currently use oral contraceptives, the attributable risk is very small because the incidence in this age range is very low. There is no difference between the risk of oral contraceptives of the third and second generation; only first generation oral contraceptives seem to be associated with a higher risk. This small increase in risk may be further reduced by efforts to control cardiovascular risk factors, particularly high blood pressure. Key messages This study shows a slightly increased relative risk of thromboembolic stroke in women currently using oral contraceptives compared with women not using them. The high dose oestrogen pills carry a higher risk than the low dose formulations, irrespective of the type of progestin The absolute risk of occlusive stroke for women who currently use modern oral contraceptives is very small—that is, the incidence in this age range is very low and not different between second and third generation oral contraceptives This small increase in risk can be controlled by avoiding prescription of oral contraceptives to women who have evidence of cardiovascular disease, in particular high blood pressure

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.

The Menopause Rating Scale (MRS) as outcome measure for hormone treatment? A validation study

BackgroundThe Menopause Rating Scale is a health-related Quality of Life scale developed in the early 1990s and step-by-step validated since then. No methodologically detailed work on the utility of the scale to assess health-related changes after treatment was published before.MethodWe analysed an open, uncontrolled post-marketing study with over 9000 women with pre- and post-treatment data of the MRS scale to critically evaluate the capacity of the scale to measure the health-related effects of hormone treatment independent from the severity of complaints at baseline.ResultsThe improvement of complaints during treatment relative to the baseline score was 36% in average. Patients with little/no complaints before therapy improved by 11%, those with mild complaints at entry by 32%, with moderate by 44%, and with severe symptoms by 55% – compared with the baseline score. We showed that the distribution of complaints in women before therapy returned to norm values after 6 months of hormone treatment. We also provided weak evidence that the MRS results may well predict the assessment of the treating physician. Limitations of the study, however, may have lead to overestimating the utility of the MRS scale as outcome measure.ConclusionThe MRS scale showed some evidence for its ability to measure treatment effects on quality of life across the full range of severity of complaints in aging women. This however needs confirmation in other and better-designed clinical/outcome studies.

Oral contraceptives and liver cancer: Results of the multicentre international liver tumor study (MILTS)

Many, but not all, previous epidemiological studies indicated a greater risk of hepatocellular cancer (HCC) in women who have used combined oral contraceptives for a long period of time, but no one has analyzed this risk based upon use of different formulations. It was decided to analyze specifically the risk of OC containing cyproterone acetate (CPA) after toxicological experiments in animals found hints for a potential genotoxicity. This report describes the risk associated with ever having used combined oral contraceptives (OC) among 317 cases of primary hepatocellular cancer (HCC) in women under age 65, compared with 1060 age-matched hospital and 719 population controls in a case-control study, which was conducted in six European countries. The adjusted odds ratio (unconditional logistic regression) for ever having used any OC was found to be 0.75 (0.54 to 1.03) when all cases were compared with all controls, and compared to hospital and population controls separately: 1.13 (0.86 to 1.48) and 0.78 (0.59 to 1.03), respectively. The adjusted odds ratios for OC containing all progestins of the CPA group were 0.89 (0.49 to 1.61); and 0.89 (0.37 to 2.18) for OC containing only CPA. There was no increase in risk for HCC with increasing duration of OC use among the different groups of OCs in the total group of cases with pooled controls. The risk estimates were not related to time since first or last use of any of the types of OCs considered. The most important risk factors for HCC were confirmed as a prior history of hepatitis B and C (adjusted odds ratio 3.1 (2.2; 4.3) and 37.9 (20.2; 70.9) for HBV and HCV, respectively). In the small subgroup of HCC cases without liver cirrhosis and with negative serology for HBV and HCV, there was evidence of an association with duration of OC use. No such trend was observed for the CPA group of OCs. Altogether, there is no evidence for an increased risk of HCC associated with CPA or CPA-like OCs. Oral contraceptives in the aggregate may enhance the risk of liver carcinomas not associated with HBV or HCV infection, but if so, this is an extremely rare adverse effect of their use.

Could preferential prescribing and referral behaviour of physicians explain the elevated thrombosis risk found to be associated with third generation oral contraceptives

Background—Recently published case–control studies on third versus second generation oral contraceptives showed a slightly increased risk for venous thromboembolism (VTE) and led to a discussion about biases or confounders external to the study such as, preferential prescribing of third generation pills to women at higher risk and differential diagnostic behaviour.