Kenneth D MacRae

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 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

ALCOHOL CONSUMPTION, PREGNANCY, AND LOW BIRTHWEIGHT

Abstract The relation between alcohol consumption during pregnancy and birthweight was investigated prospectively in 900 white women. With adjustment for social class and cigarette smoking, women drinking more than 100 g alcohol a week had a risk of delivering a baby on or below the 10th centile more than double that of women drinking less than 50 g a week. The effect of alcohol was synergistic with that of smoking. Drinking at about the time of conception seems to be important for this effect; therefore, health education should be directed at reducing alcohol consumption before pregnancy.

Trends in sexual behaviour and risk factors for HIV infection among homosexual men, 1984-7.

To assess whether the spread of infection with HIV can be reduced by changes in behaviour among groups most at risk because of their sexual practices sexual behaviour was monitored among 1050 homosexual men tested for HIV infection at a genitourinary medicine clinic in west London from November 1984 to September 1987. Four cohorts, defined by date of presentation, were studied by questionnaire at their presentation, and blood samples were analysed. Between the first and last cohorts there was a considerable fall in the proportion reporting casual relationships (291/329 (88%) v 107/213 (50%] and high risk activities, such as anoreceptive intercourse with casual partners (262/291 (90%) v 74/106 (70%], with the greatest changes occurring before the government information campaign began in 1986. Nevertheless, half of the men in the last cohort studied reported having casual partners. Multiple logistic regression showed that behavioural risk factors for HIV infection most closely resembled those for hepatitis B and that previous sexually transmitted diseases (syphilis, hepatitis B, and anogenital herpes) were themselves independent risk factors. A history of syphilis ranked above anoreceptive intercourse as the strongest predictor of HIV infection. Actively bisexual men showed a much lower prevalence of HIV infection (3/57, 5%) than exclusively homosexual men (113/375, 30%). Sexual behaviour among homosexual men changed during the period studied, and the incidence of HIV infection fell, although more education programmes directed at homosexual men are needed to re-emphasise the dangers of infection.

Heterosexual relationships and condom-use in the spread of sexually transmitted diseases to women.

OBJECTIVES--To examine the effect of patient-defined non-regular heterosexual relationships on the incidence of sexually transmitted diseases and other genital infections in women and the role of condom use in the prevention of their spread. DESIGN--A cross-sectional study of sexual behaviour reported by a standardised self-administered questionnaire in new patients who presented for screening and diagnosis. SETTING--A genitourinary medicine clinic in West London. SUBJECTS--938 consecutive newly attending women who completed a sexual behaviour questionnaire in 1992. MAIN OUTCOME MEASURES--Variables relating to socio-demographic status, sexual behaviour, condom use, sexually transmitted diseases and other genital infections stratified by the reporting of non-regular partners. RESULTS--We found that women who reported non-regular sexual partners were more likely to be single (p = 0.0001), white (p < 0.0001), have had coitarche before 17 years of age (p = 0.003) and many more sexual partners both in the last year and in their life-time (p < 0.0001) and were more likely to practise fellatio (p < 0.0001), anal penetration (p = 0.004) and to be smokers (p < 0.0001). Paradoxically, the incidence of sexually transmitted diseases and other genital infections was no higher in this group than in the group of women who did not have non-regular partners. Increasing condom use with regular partners correlated with decreasing incidence of gonorrhoea (p < 0.001), chlamydial infection (p < 0.01) and trichomoniasis (p < 0.02), but increasing condom use with non-regular partners did not show this trend. CONCLUSIONS--Regular heterosexual partners play the major role in transmission of bacterial sexually transmitted diseases to women. This is significantly influenced by use of condoms.

Third generation oral contraceptive pills

Is the scare over the increased risk of thrombosis justified? Britains Committee on Safety of Medicines has issued a recommendation that combined oral contraceptives containing the so called third generation progestogens, desogestrel and gestodene, should no longer be routinely prescribed. The committee came to this conclusion after examining the data from three unpublished studies, two of which have not been completed. These studies--an international study organised by the World Health Organisation; the European transnational study of oral contraceptives, which is funded by the pharmaceutical company Schering AG; and a study of data from the United Kingdom general practice research database (formerly known as VAMP)--were designed to examine whether the risk of vascular disease in women taking the newer oral contraceptive pills differed from that in women taking the slightly older pills containing predominantly the progestogen levonorgestrel. …

Lowered risk of dying of heart attack with third generation pill may offset risk of dying of thromboembolism

Reported in this letter are the final results of a transnational case-control study on oral contraceptives (OCs) and myocardial infarction. 182 women 16-44 years of age with myocardial infarction were recruited to the study at 16 European centers in 1993-96; 635 hospital and community-based healthy women matched by age group and site served as controls. Documented in linear trend analysis was a clear decrease in risk from first to third generation OCs. The odds ratios (ORs) were 4.66 (95% confidence interval (CI) 1.52-14.33) for women who used first-generation OCs 2.99 (95% CI 1.51-5.91) for second-generation OCs and 0.85 (95% CI 0.30-2.39) for third-generation pills. The OR for current use of third-generation OCs compared with current use of second-generation pills was 0.28 (95% CI 0.09-0.87). Finally the OR for the risk of myocardial infarction was 7.2 (95% CI 4.6-11.4) when current smoking was adjusted for OC use. The expected reduction in deaths from myocardial infarction associated with third-generation OCs should offset any excess deaths associated with venous thromboembolism.

Sexual relationships, risk behaviour, and condom use in the spread of sexually transmitted infections to heterosexual men.

OBJECTIVE: To examine the effect of patient defined non-regular sexual relationships and other risk behaviours on the incidence of sexually transmitted infections in heterosexual men and the role of condom use in the prevention of their spread. DESIGN: A prospective cross sectional study of sexual behaviour reported by a standardised self administered questionnaire in new patients who presented for screening and diagnosis. SETTING: A genitourinary medicine clinic in west London. SUBJECTS: 957 consecutive newly attending heterosexual men who completed a sexual behaviour questionnaire in 1993/94. MAIN OUTCOME MEASURES: Variables relating to sociodemographic status, sexual behaviour, condom use, sexually transmitted infections and testing for HIV infection, stratified by the reporting of non-regular partners. RESULTS: We found that the 65% of men who reported non-regular sexual partners were more likely to be white collar class (d = 7.5%, 95% CI = 1.3, 13.7) and to have had sexual intercourse with non-United Kingdom born women (d = 7.8%, 95% CI = 3.5, 12.2). They also reported coitarche before 16 years of age (d = 13.4%, 95% CI = 8.0, 18.8) and many more sexual partners both in the last year (d = 13.1%, 95% CI = 10.2, 16.0) and in their lifetime (d = 27.9%, 95% CI = 21.6, 34.2). They were significantly more likely to practise anal intercourse (d = 8.7%, 95% CI = 3.3, 14.1), to smoke (d = 16.3%, 95% CI = 9.8, 22.6), to drink alcohol (d = 4.9%, 95% CI = 1.2, 8.6), and to have chlamydial infection (d = 5.7%, 95% CI = 2.2, 9.2), of which 30% was subclinical. Increasing condom use with regular partners correlated with decreasing incidence of urethral infection (gonorrhoeal and/or chlamydial infection) (p < 0.03) and candidal balanitis (p < 0.03) and a greater likelihood of no infection being detected (p = 0.0002). Use of condoms with non-regular partners was much more frequent than with regular partners (d = 21.4%, 95% CI = 16.7, 26.1). However, we found evidence of oral transmission of urethral gonorrhoea and chlamydial infection among men who reported always using condoms. HIV infection was found in only two men (0.2%), both of whom reported intercourse with non-United Kingdom born women. CONCLUSIONS: Heterosexual men who reported non-regular sexual relationships compensated for their increased risk lifestyle by using condoms more frequently and showed only an increased incidence of chlamydial infection. More consistent condom use with regular partners was significantly associated with the absence of sexually transmitted infection. These findings suggest that transmission between regular partners has been underestimated.

Sexual lifestyle and clinical findings related to HTLV-III/LAV status in homosexual men.

A study of 304 sexually active homosexual men, most of whom had multiple casual partners, showed that receptive anogenital intercourse, independent of anal bleeding, was the only risk factor for HTLV-III/LAV transmission. There was no evidence that HTLV-III/LAV infection, measured by seropositivity, was transmitted by oroanal or orogenital routes, or that insertive penile intercourse constituted a risk. The strongest predictor of seropositivity proved to be homosexual activity for more than five years, which may lead to enhanced susceptibility to infection. Sexual exposure to European men seemed to be even more hazardous than sexual exposure to men from the United States of America, and emphasised the epidemiological importance of the promiscuous homosexual abroad. Skin complaints were the most common presenting symptoms in men with antibody to HTLV-III/LAV. Extrainguinal lymphadenopathy was the commonest sign, which was present in just under half of those who were seropositive. More than one quarter of seropositive patients had had sexual intercourse with a woman in the five years before being tested.