Investigation of Relation between Use of Oral Contraceptives and Thromboembolic Disease. A Further Report

The results of a previous study of the use of oral contraceptives by married women discharged from hospital with a diagnosis of thromboembolic disease in the years 1964–6 were reported by us last year. The present paper adds results relating to patients discharged during 1967 and a few data, that could not be sought previously, for patients discharged with cerebral or coronary thrombosis from three of the hospitals in the earlier period.Of 84 patients with deep-vein thrombosis or pulmonary embolism 42 (50%) had used oral contraceptives during the month preceding the onset of their illness, while only 23 of the 168 controls (14%) had done so. No differences in risk were found either for the types of preparation or for the duration of use. After allowance for age and height, the patients with venous thromboembolism were about 10 lb. (4,535 g.) heavier than the control patients, irrespective of whether they were using oral contraceptives or not. No appreciable difference was found between the smoking habits of patients with and without venous thromboembolism treated during 1967, nor between women who were using oral contraceptives and those who were not. The trend in hospital admissions for venous thromboembolism with time corresponded to the trend in the use of oral contraceptives, and there was no evidence to suggest that the number of admissions was affected by publicity about the risk of using the preparations. Of 19 patients with cerebral thrombosis 11 (58%) had been using oral contraceptives, compared with an expected figure of 3.5 from the experience of the control subjects. All the published data (clinical, angiographic, and post-mortem) show that the thrombosis affects the cerebral arteries rather than the cerebral veins. Of 17 patients with coronary thrombosis 2 (12%) had been using oral contraceptives, compared with an expected figure of 2.1. The patients with coronary thrombosis smoked more than the control patients and were, on average, 8.3 lb. (3,765 g.) heavier than control women of the same age and height.The new evidence strengthens the belief that oral contraceptives are a cause of venous thromboembolism and cerebral thrombosis but does not indicate that they are a cause of coronary thrombosis.     

Thrombosis and Oral Contraceptives: Possible Predisposition

The coagulation factors and components of the fibrinolytic system were examined in 31 women with a previous history of phlebographically-verified thrombosis during the use of oral contraceptives of the combined type. Special attention was given to the histochemically-determined fibrinolytic activator content of the wall of biopsy specimens of superficial veins. None of the patients was taking contraceptives at the time of the investigation. Pathological changes, particularly in the fibrinolytic defence system, were found in most of the patients. They may be regarded as predisposed to thrombosis, and one might wonder whether these patients would sooner or later have had their thrombosis even if they had not used contraceptives. The concentration of antithrombin III was normal, indicating that this test is of no value for detecting patients predisposed to thrombosis, who should preferably not take oral contraceptives.     

Oral contraceptive use and venous thromboembolism: absence of an effect of smoking.

We conducted a case-control study to test the hypothesis that women smokers who use oral contraceptives have an increased risk of developing venous thrombosis. Patients and controls were drawn from two sets of hospital patients already included in the Boston Collaborative Drug Surveillance Programme. Sixty patients with uncomplicated thromboembolism were matched with 180 controls with other diagnoses; all were premenopausal women taking oral contraceptives. Patients with conditions that might predispose to thromboembolism or be related to smoking were excluded. We found no association between smoking habits and thromboembolism. Similarly, we found no association between thromboembolism, smoking, and duration of oral contraceptive use. Thus we conclude that differences in fibrinolytic activity between smokers and non-smokers are not major factors in the aetiology of uncomplicated thromboembolism in women using oral contraceptives.     

Oral contraceptives,pregnancy, and endogenous oestrogen in gall stone disease--a case-control study.

A case-control study of gall stone disease in women in relation to use of contraceptives, reproductive history, and concentrations of endogenous hormones was undertaken. The study population comprised 200 hospital patients with newly diagnosed gall stone disease, 182 individually matched controls selected from the community, and 234 controls who were patients in hospital. Use of oral contraceptives was associated with an increased risk of developing gall stones among young subjects but a decreased risk among older subjects. The risk of developing gall stone disease increased in association with increasing parity, particularly among younger women. The risk fell with increasing age at first pregnancy, independent of parity. Mean urinary excretion over 24 hours of oestrone, but not of pregnanediol, was significantly (p less than 0.05) greater for postmenopausal patients than controls. The age dependence of the relative risk associated with exposure to oral contraceptives and pregnancy suggests that there are subpopulations of women susceptible to early formation of gall stones after exposure to either oral contraceptives or pregnancy.     

Determinants of contraceptive use in Nepal

This 1981 study is the 1st of its kind in Nepal. Analysis using a logit-linear model showed that contraceptive use in Nepal depends on many factors. Women aged 35-49 are 3 times more likely than women aged 15-24 to use contraceptives. Women with 4 or more children are 8 times more likely to use contraceptives than women with 1 or no children, and 2.5 times more likely than women with 2 or 3 children. The use of contraceptives is greatest among women whose offspring includes more sons than daughters, and least among women whose offspring are all daughters. Women who desire no more children are 5 to 6 times more likely to use contraceptives than women who desire more children. Women who have discussed desired family size with their husbands are more than 4 times more likely to use contraceptives than women lacking this type of communication. Women with some schooling are twice as likely to use contraceptives as women with no schooling. Contraceptive use is higher among women who do nonfarm work than farm work, and higher still among women who do not work. Urban women were almost twice as likely to use contraceptives as rural women. Women with less than 1 hour access to a family planning service outlet were 2 to 3 times more likely to use contraceptives than women whose access to these facilities was greater than 1 hour. The number of previous child losses per woman had no significant effect in contraceptive use. Conclusions are based on analysis of data from the Nepal Contraceptive Prevalence Survey, 1981.     

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions

Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. Design: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. Setting: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). Subjects: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). Main outcome measure: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. Results: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. Conclusion: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.

Key messages

• The use of oral contraceptives is associated with an increased risk of cerebral venous sinus thrombosis
• This risk of cerebral venous sinus thrombosis in women who use oral contraceptives is larger if there is an additional hereditary prothombotic factor (protein C, S, or antithrombin deficiency, factor V Leiden mutation)
• The association between oral contraceptives, thrombophilia, and deep vein thrombosis is also valid for cerebral sinus thrombosis
• Women do not need to stop using oral contraceptives as the absolute risk of cerebral sinus thrombosis is very small

     

Risk of venous thromboembolism among users of third generation oral contraceptives compared with users of oral contraceptives with levonorgestrel before and after 1995: cohort and case-control analysis

ObjectiveTo compare the risk of idiopathic venous thromboembolism among women taking third generation oral contraceptives (with gestodene or desogestrel) with that among women taking oral contraceptives with levonorgestrel.DesignCohort and case-control analyses derived from the General Practice Research Database.SettingUK general practices, January 1993 to December 1999.ParticipantsWomen aged 15-39 taking third generation oral contraceptives or oral contraceptives with levonorgestrel.ResultsThe adjusted estimates of relative risk for venous thromboembolism associated with third generation oral contraceptives compared with oral contraceptives with levonorgestrel was 1.9 (95% confidence interval 1.3 to 2.8) in the cohort analysis and 2.3 (1.3 to 3.9) in the case-control study. The estimates for the two types of oral contraceptives were similar before and after the warning issued by the Committee on Safety of Medicines in October 1995. A shift away from the use of third generation oral contraceptives after the scare was more pronounced among younger women (who have a lower risk of venous thromboembolism) than among older women. Fewer cases of venous thromboembolism occurred in 1996 and later than would have been expected if the use of oral contraceptives had remained unchanged.ConclusionsThese findings are consistent with previously reported studies, which found that compared with oral contraceptives with levonorgestrel, third generation oral contraceptives are associated with around twice the risk of venous thromboembolism.     

Estimate of Venous Thromboembolism and Related-Deaths Attributable to the Use of Combined Oral Contraceptives in France

Purpose

To estimate the number of venous thromboembolic events and related-premature mortality (including immediate in-hospital lethality) attributable to the use of combined oral contraceptives in women aged 15 to 49 years-old between 2000 and 2011 in France.

Methods

French data on sales of combined oral contraceptives and on contraception behaviours from two national surveys conducted in 2000 and 2010 were combined to estimate the number of exposed women according to contraceptives generation and age. Absolute risk of first time venous thromboembolism in non-users of hormonal contraception and increased risk of thromboembolism in users vs. non-users of hormonal contraception were estimated on the basis of literature data. Finally, immediate in-hospital lethality due to pulmonary embolism and premature mortality due to recurrent venous thromboembolism were estimated from the French national database of hospitalisation and literature data.

Results

In France, more than four million women are daily exposed to combined oral contraceptives. The mean annual number of venous thromboembolic events attributable to their use was 2,529 (778 associated to the use of first- and second-generation contraceptives and 1,751 to the use of third- and fourth-generation contraceptives), corresponding to 20 premature deaths (six with first- and second-generation contraceptives and fourteen with third- and fourth-generation contraceptives), of which there were eight to nine immediate in-hospital deaths. As compared to the use of first- and second-generation contraceptives, exposure to third- and fourth-generation contraceptives led to a mean annual excess of 1,167 venous thromboembolic events and nine premature deaths (including three immediate in-hospital deaths).

Conclusions

Corrective actions should be considered to limit exposure to third- and fourth-generation contraceptives, and thus optimise the benefit-risk ratio of combined oral contraception.     

An epidemiological study of oral contraceptives and breast cancer

During 1968-77, 707 women aged 16-50 years with newly diagnosed breast cancer and 707 matched controls were interviewed at eight teaching hospitals in London and Oxford about their use of oral contraceptives. Eighty-six of the patients with breast cancer were matched with controls with gall-bladder disease; these subjects were omitted from the main analyses, which thus related to 621 case-control pairs.The results were reassuring. A few statistically significant differences in oral contraceptive use were found between the breast cancer and control groups, but the data were subdivided in many ways, so that some “significant” differences would have been expected to occur by chance. The only subgroup in which the evidence for a positive association between pill use and breast cancer was at all convincing comprised women aged 46-50 years, but trends in those aged 41-45 were by and large in the opposite direction and results of combined analysis gave no cause for concern.Information on clinical stage was available for 487 patients with breast cancer treated before the end of 1975. Those who had never used oral contraceptives had appreciably more advanced tumours at presentation than those who had been using the pill during the year before detection of the lump, while past users of the pill occupied an intermediate position. This difference in staging was reflected in the pattern of survival. Oral contraceptives may have had a beneficial effect on tumour growth and spread, though diagnostic bias could not be definitely excluded.     

Hormonal contraceptive use and mate retention behavior in women and their male partners

Female hormonal contraceptive use has been associated with a variety of physical and psychological side effects. Women who use hormonal contraceptives report more intense affective responses to partner infidelity and greater overall sexual jealousy than women not using hormonal contraceptives. Recently, researchers have found that using hormonal contraceptives with higher levels of synthetic estradiol, but not progestin, is associated with significantly higher levels of self-reported jealousy in women. Here, we extend these findings by examining the relationship between mate retention behavior in heterosexual women and their male partners and women's use of hormonal contraceptives. We find that women using hormonal contraceptives report more frequent use of mate retention tactics, specifically behaviors directed toward their partners (i.e., intersexual manipulations). Men partnered with women using hormonal contraceptives also report more frequent mate retention behavior, although this relationship may be confounded by relationship satisfaction. Additionally, among women using hormonal contraceptives, the dose of synthetic estradiol, but not of synthetic progesterone, positively predicts mate retention behavior frequency. These findings demonstrate how hormonal contraceptive use may influence behavior that directly affects the quality of romantic relationships as perceived by both female and male partners.     

Recurrence of Venous Thromtoembolic Disease and Use of Oral Contraceptives

In 1969 this department reported on 42 women who had developed “idiopathic” venous thromboembolism while using oral contraceptives and 42 women who had developed the disease in the absence of such exposure. We have traced the subsequent history of these women to obtain information about recurrence of the disease.During the follow-up period the risk of recurrence of thromboembolism during pregnancy or the puerperium appeared to be much the same irrespective of whether or not oral contraceptives had been in use at the time of the index attack. Recurrences unassociated with childbearing however, occurred about four times more often among women who had not been using oral contraceptives at the time of the index attack than among women who had been doing so. None of these findings was influenced by the use of oral contraceptives during the follow-up period, since exposure to the preparations was negligible after the index attack.     

Lessons from an audit of unplanned pregnancies.

To determine the effectiveness of contraceptive use a two year audit of pregnant women registered in one group practice was carried out. The methods of contraception used by women with unplanned pregnancies were studied and the rates of failure assessed. Of the 518 pregnancies during the study, 187 (36%) were unplanned. Unplanned pregnancies were most common in the 15-19 age group (54 out of 187), and women aged under 25 used contraceptives less reliably than women aged 25 and over. The combined pill was the most effective method of contraception in all age groups. The methods that resulted in most unplanned pregnancies were the sheath in women aged 25 and over and incorrect use of oral contraceptive or no contraception in those aged under 25. The fear of side effects was an important reason why women did not use the combined pill, being cited by 22 out of 134 women, and inappropriate medical advice was cited by a further 20 women. More discussion between doctors and patients and readily available information on the use of oral contraceptives might help to reduce the number of unplanned pregnancies.     

Postoperative Thromboembolism and the Use of Oral Contraceptives

We have previously reported the results of a retrospective study of the relationship between oral contraceptives and deep vein thrombosis and pulmonary embolism occurring in the absence of an evident predisposing cause. The present paper describes a similar investigation of the relationship between oral contraceptives and thromboembolism following certain surgical procedures.Of 30 patients with thromboembolism, 12 (40%) had been using oral contraceptives during the month preceding surgery, while only 9 of 60 matched controls (15%) had been doing so. From these data it is estimated that the risk of postoperative thromboembolism is increased threefold to fourfold by the use of contraceptive steroids.It is recognized that few of the episodes of deep vein thrombosis and pulmonary embolism that occur postoperatively are detectable clinically, and that not all of these are recorded in discharge summaries or diagnostic indexes. Despite these considerations, we have been unable to detect any important bias in the data which could account for the observed association between oral contraceptives and the development of postoperative thromboembolism.     

Blood pressure and contraceptive use

In a survey of 461 women routinely attending family planning clinics those taking oral contraceptives had significantly higher mean systolic and diastolic blood pressures than those using non-hormonal contraception. There appeared to be a dose-response relation of blood pressure to the progestogen component of two oral contraceptives with an identical 30 μg ethinyloestradiol component. This supports the idea that the progestogen as well as the oestrogen component has an aetiological role in the rise in blood pressure. There was a significant correlation of blood pressure with duration of current use of oral contraceptive but not with total duration of use. There was also a significant negative correlation of blood pressure with time since oral contraceptives were last taken, and women who had stopped using oral contraceptives over a month previously had similar blood pressures to those who had never taken them. In women taking oral contraceptives those who had either a history of hypertension in pregnancy or a family history of hypertension had significantly higher mean blood pressures than those who did not. Both systolic and diastolic blood pressures correlated independently with weight and body mass index, but controlling for the effect of this and age did not affect the above relations. No significant differences in mean blood pressures were found between different ethnic groups, and there was no relation of blood pressure to reported marital state, social class, parity, smoking, or alcohol use.Any oral contraceptive that has a less adverse effect on blood pressure has implications for general prescribing policy; thus even small differences in the progestogen contents of low-dose oestrogen pills may be important.     

Altered haemorheology in oral-contraceptive users.

The haemorheological profile of the menstrual cycle was determined in 12 women who did not take oral contraceptives and compared with that in two groups of women (n = 8 and n = 30) who had been taking oral contraceptives for at last six months. Packed cell volume, platelet count, erythrocyte deformability, plasma fibrinogen concentration, and plasma and whole-blood viscosity varied cyclically throughout the menstrual cycle in the 12 non-users. This variation was abolished by the use of oral contraceptives, and the values of these indices were raised by an amount likely to predispose to thrombosis.     

Injectable and Oral Contraceptive Use and Cancers of the Breast,Cervix, Ovary,and Endometrium in Black South African Women: Case–Control Study

Background

Oral contraceptives are known to influence the risk of cancers of the female reproductive system. Evidence regarding the relationship between injectable contraceptives and these cancers is limited, especially in black South Africans, among whom injectable contraceptives are used more commonly than oral contraceptives.

Methods and Findings

We analysed data from a South African hospital-based case–control study of black females aged 18–79 y, comparing self-reported contraceptive use in patients with breast (n = 1,664), cervical (n = 2,182), ovarian (n = 182), and endometrial (n = 182) cancer, with self-reported contraceptive use in 1,492 control patients diagnosed with cancers with no known relationship to hormonal contraceptive use. We adjusted for potential confounding factors, including age, calendar year of diagnosis, education, smoking, alcohol, parity/age at first birth, and number of sexual partners. Among controls, 26% had used injectable and 20% had used oral contraceptives. For current and more recent users versus never users of oral or injectable contraceptives, the odds ratios (ORs) for breast cancer were significantly increased in users of oral and/or injectable contraceptives (OR 1.66, 95% CI 1.28–2.16, p<0.001) and separately among those exclusively using oral (1.57, 1.03–2.40, p = 0.04) and exclusively using injectable (OR 1.83, 1.31–2.55, p<0.001) contraceptives; corresponding ORs for cervical cancer were 1.38 (1.08–1.77, p = 0.01), 1.01 (0.66–1.56, p = 0.96), and 1.58 (1.16–2.15, p = 0.004). There was no significant increase in breast or cervical cancer risk among women ceasing hormonal contraceptive use ≥10 y previously (p = 0.3 and p = 0.9, respectively). For durations of use ≥5 y versus never use, the ORs of ovarian cancer were 0.60 (0.36–0.99, p = 0.04) for oral and/or injectable contraceptive use and 0.07 (0.01–0.49, p = 0.008) for injectable use exclusively; corresponding ORs for endometrial cancer were 0.44 (0.22–0.86, p = 0.02) and 0.36 (0.11–1.26, p = 0.1).

Conclusions

In this study, use of oral and of injectable hormonal contraceptives was associated with a transiently increased risk of breast and cervical cancer and, for long durations of use, with a reduced risk of ovarian and endometrial cancer. The observed effects of injectable and of oral contraceptives on cancer risk in this study did not appear to differ substantially. Please see later in the article for the Editors'' Summary     

Pregnancy induced hypertension: evidence for increased cell membrane permeability to sodium.

In a cross sectional study of 137 women of childbearing age (16-40) the effects of normal pregnancy, hypertensive pregnancy, and oral contraceptives on red cell electrolyte content and sodium efflux rates were examined and the results compared with values in a control group of normotensive, non-pregnant women. Efflux rate constants were significantly increased in normotensive pregnancy and in women taking oral contraceptives. This was associated with a significant increase in sodium permeability in the contraceptive group. A much larger increase in sodium permeability and efflux rate constant was seen in the hypertensive group. The results permit a hypothesis that the hormonal changes induced by pregnancy and oral contraceptives increase membrane permeability to sodium and stimulate sodium efflux. The rise in blood pressure associated with use of oral contraceptives may have a similar aetiology to that occurring in pregnancy induced hypertension.     

Histochemical and immunohistochemical detection of putative preneoplastic liver foci in women after long-term use of oral contraceptives

Localized areas with altered enzyme patterns were observed in liver tissue surrounding focal nodular hyperplasia in women after long-term use of oral contraceptives. These localized lesions were of three different types. Type I lesions were characterized by glycogen storage, a reduction in ATPase and an increase in gamma-glutamyltranspeptidase (gamma-GT) and UDP-glucuronyltransferase (UDP-GT) detected immunohistochemically. Type II lesions, which were morphologically very similar to small hyperplastic nodules, showed only a decreased ATPase reaction. Type III lesions showed an increase in gamma-GT (detected histochemically) and a slight reduction in ATPase. The results indicated that in human liver from patients given oral contraceptives long-term, localized lesions with altered enzyme patterns may occur which are very similar to those observed in animal models during experimental hepatic carcinogenesis.     

Epidemiology of endometriosis in women attending family planning clinics.

OBJECTIVE--To describe the epidemiology of endometriosis in women attending family planning clinics with special reference to contraceptive methods. DESIGN--Non-randomised cohort study with follow up of subjects for up to 23 years. Disease was measured by first hospital admission rates since endometriosis can be diagnosed with accuracy only at laparotomy or laparoscopy. SETTING--17 family planning centres in England and Scotland. SUBJECTS--17,032 married white women aged 25-39 years at entry during 1968-74 who were taking oral contraceptives or using an intrauterine device or diaphragm. About 99% of the women approached agreed to participate and annual loss to follow up was about 0.3%. MAIN OUTCOME MEASURES--Diagnosis of endometriosis, age, parity, and history of contraceptive use. RESULTS--Endometriosis was significantly related to age, peaking at ages 40-44 (chi 2 for heterogeneity = 30.9, p < 0.001). Endometriosis was not linked to duration of taking oral contraceptives. Nevertheless, the risk of endometriosis was low in women currently taking oral contraceptives (relative risk 0.4; 95% confidence interval 0.2 to 0.7), but higher in women who had formerly taken them (1.8; 1.0 to 3.1 in women who had stopped 25-48 months previously) compared with women who had never taken the pill. A similar pattern was seen for use of intrauterine devices (relative risk 0.4 (0.2 to 0.7) in current users and 1.4 (0.4 to 3.2) in users 49-72 months previously compared with never users). No association was found between endometriosis and use of the diaphragm. CONCLUSIONS--Oral contraceptives seem to temporarily suppress endometriosis. Endometriosis may be diagnosed late in women using intrauterine devices as pain and bleeding occur with both.