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.     

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.     

Breast cancer and oral contraceptives: findings in Oxford-Family Planning Association contraceptive study.

Among the 17 032 women taking part in the Oxford-Family Planning Association contraceptive study, 72 were first diagnosed as having breast cancer between the date they were admitted to the study and 1 September 1980. The relative risk of developing the disease in women who had used oral contraceptives in comparison with those who had never used them was estimated to be 0.96 (95% confidence limits 0.59 to 1.63). Among women aged under 35 years, the corresponding relative risk (based on only 14 women with breast cancer) was estimated to be 0.61. No relation was apparent between the risk of developing breast cancer and duration of oral-contraceptive use or interval since first oral-contraceptive use in any age group. The data in this study are thus reassuring; but observations based on women with long-term use of oral contraceptives, especially those starting to use the preparations at an early age, are few.     

Oral contraceptives and fatal subarachnoid haemorrhage.

A case-control study was conducted of the deaths from subarachnoid haemorrhage (SAH) in women aged 15-44 in England and Wales in 1976. There was a small excess of oral contraceptive use by the women who died from SAH compared with their generally healthy practice-matched controls; this was not, however, statistically significant. Out of 134 women who died from SAH, 34 had a history of hypertension compared with only six of their controls. Renal disease and pre-eclamptic toxaemia were more commonly associated with hypertension in the dead women than in controls. No change in the annual mortality from SAH has been observed in the past 20 years such as might have been expected if the risks were high. Although current or past use of oral contraceptives may have increased the blood pressure and risk of SAH in a few women, the most important factor in determining this risk was hypertension. SAH should thus probably not be regarded as serious cause for concern in healthy non-hypertensive women using oral contraceptives.     

Breast cancer and oral contraceptives: findings in Royal College of General Practitioners' study.

The incidence of breast cancer was studied among women taking part in the continuing cohort study organised by the Royal College of General Practitioners. An overall relative risk of 1.19 (not significant) was found in those who had used oral contraceptives. The risk ratio in women under 35 years old was 2.81, but this too was not significant. There was evidence that the estimated increased risk for younger women could be a chance occurrence. No convincing evidence of any adverse effects of oral contraceptives on breast cancer has been shown, but because of the long latent period of this tumour there is a need for longer observation.     

Oral contraceptives and death from myocardial infarction.

We investigated 219 deaths from myocardial infarction in women under the age of 50. Their histories were compared with those of living age-matched controls selected from the same general practices. The frequency of use of oral contraceptives during the month before death was significantly greater in the group with infarction than during the corresponding month in the control group and the average duration of use was longer. No information of cigarette smoking was available but the proportion of women being treated for hypertension or diabetes was greater among those who died than among the controls. This did not alter the overall conclusion that the risk of fatal myocardial infarction was greater in the women using oral contraceptives, particularly in the older age groups.     

Ovarian neoplasms,functional ovarian cysts,and oral contraceptives.

The incidence of ovarian neoplasms and functional ovarian cysts diagnosed at laparotomy or laparoscopy among the 17,000 women taking part in the Oxford Family Planning Association contraceptive study was investigated. Epithelial cancer of the ovary was only 25% as common among those who had ever taken oral contraceptives as those who had never done so (95% confidence interval 8% to 67%). There was little evidence of any important association between use of oral contraceptives and benign teratoma or cystadenoma. Functional cysts of the ovary occurred much less commonly in women who had recently (in the six months preceding diagnosis) taken combined oral contraceptives (but not in those who had taken progestogen only oral contraceptives) than in those who had never taken oral contraceptives or had taken them in the past. This protective effect was more pronounced for corpus luteum cysts (78% reduction; 95% confidence interval 47% to 93%) than for follicular cysts (49% reduction; 95% confidence interval 20% to 70%). It is estimated that about 28 (95% confidence interval 16 to 35) operations for functional ovarian cysts are avoided among every 100,000 women who take oral contraceptives each year.     

Erythema nodosum associated with pregnancy and oral contraceptives.

Erythema nodosum recurred in a woman during each of her four pregnancies and every time she was started on oral contraceptives. The lesions always disappeared in the fifth month of gestation or when contraceptives were withdrawn. Erythema nodosum is mediated by immune mechanisms, and both pregnancy and oral contraceptive use can interfere with the immune system. The concentrations of oestrogen and progesterone or the ratio between them may be critical to the development of erythema nodosum. The observation that the lesions spontaneously resolved in the fifth month of pregnancy supports this hypothesis.     

Interaction between anticoagulants and contraceptives: an unsuspected finding.

To assess the effects of oral contraceptives on anticoagulant treatment the prothrombin times of 12 patients were measured while they were taking both drugs simultaneously and while they were taking only anticoagulants. The mean prothrombin time ratio was significantly higher when patients were taking both drugs than when they were taking only anticoagulants and their doses of anticoagulant were significantly lower. During both periods most of the prothrombin values remained in the therapeutic range. These findings suggest that, contrary to the common belief that oral contraceptives diminish the effects of anticoagulants, contraceptives in fact potentiate the action of the anticoagulants.     

Involuntary movements in patients taking oral contraceptives

Involuntary movements developed in five women taking oral contraceptives. In one, the sudden onset of a unilateral disturbance suggested a cerebral thrombosis; this case is considered to be a further example of the increased risk of cerebrovascular disease associated with oral contraception. The four other patients suffered a relapse of Sydenham''s chorea between one and four months after starting an oral contraceptive regimen. Possibly an underlying vascular mechanism was responsible for these relapses.     

Oral contraceptives and the risk of gallbladder disease: a comparative safety study

Background

Recent concerns have been raised about the risk of gallbladder disease associated with the use of drospirenone, a fourth-generation progestin used in oral contraceptives. We conducted a study to determine the magnitude of this risk compared with other formulations of oral contraceptives.

Methods

We conducted a retrospective cohort study using the IMS LifeLink Health Plan Claims Database. We included women who were using an oral contraceptive containing ethinyl estradiol combined with a progestin during 1997–2009. To be eligible, women had to have been taking the oral contraceptive continuously for at least six months. We computed adjusted rate ratios (RRs) for gallbladder disease using a Cox proportional hazards model. In the primary analysis, gallbladder disease was defined as cholecystectomy; in a secondary analysis, it was defined as hospital admission secondary to gallbladder disease.

Results

We included 2 721 014 women in the cohort, 27 087 of whom underwent surgical or laparoscopic cholecystectomy during the follow-up period. Compared with levonorgestrel, an older second-generation progestin, a small, statistically significant increase in the risk of gallbladder disease was associated with desogestrel (adjusted RR 1.05, 95% confidence interval [CI] 1.01–1.09), drospirenone (adjusted RR 1.20, 95% CI 1.16–1.26) and norethindrone (adjusted RR 1.10, 95% CI 1.06–1.14). No statistically significant increase in risk was associated with the other formulations of oral contraceptive (ethynodiol diacetate, norgestrel and norgestimate).

Interpretation

In a large cohort of women using oral contraceptives, we found a small, statistically significant increase in the risk of gallbladder disease associated with desogestrel, drospirenone and norethindrone compared with levonorgestrel. However, the small effect sizes compounded with the possibility of residual biases in this observational study make it unlikely that these differences are clinically significant.Oral contraceptives are the most popular mode of birth control among women and are used by about 100 million women worldwide.¹ Long-term use of these drugs has been associated with a variety of serious adverse events, including deep vein thrombosis, stroke and pulmonary embolism.² In addition, both estrogen and progesterone have been shown to play an important role in the formation of gallstones.^3–5 However, the relative risk of gallbladder disease associated with different formulations of oral contraceptives, including newer formulations, is unknown.Recently, there have been concerns expressed in the media about reports of gallbladder disease necessitating cholecystectomy associated with the use of drospirenone, a fourth-generation progestin.⁶ Drospirenone combined with ethinyl estradiol is primarily marketed as Yaz and Yasmin in Canada and the United States and is one of the most prescribed oral contraceptives in North America, with worldwide sales of $2 billion in 2009.⁷ The scientific evidence on the risk of gallbladder disease associated with drospirenone consists of only anecdotal or spontaneous reports in databases of adverse drug events.A possible link between drospirenone and gallbladder disease may lead to cholecystectomy and possible surgical complications.⁸ If there were a substantial risk of gallbladder disease with drospirenone, this might influence its overall risk–benefit ratio and could prompt physicians to prescribe safer alternatives. Given that women using oral contraceptives have been found to be at increased risk of gallbladder disease compared with women not using oral contraceptives,⁴ any excess risk associated with the use of drospirenone merits quantification within the context of a comparative safety study.     

Changes in breast volume during normal menstrual cycle and after oral contraceptives.

The volume of the left and right breasts was measured daily in four nulliparous women during normal menstrual cycles and after the use of oral contraceptives. Breast volume increased significantly in the second half of both normal and contraceptive-controlled cycles. The mean total change in volume throughout the cycle was 100 ml under natural conditions and 66 ml on oral contraceptives.     

Lymphocyte transformation in newborns, women and those who had used oral contraceptives.

Lymphocyte transformation, utilizing the mitotic index parameter has been assessed in newborns' cord blood, adults and women who had been on oral contraceptives and their babies. The results show that the newborns' cord blood response is significantly higher to PHA when compared with the respective adults' response. No significant difference was observed between the women taking oral contraceptives and their respective controls.     

Oral contraceptives and porphyria cutanea tarda

The clinical and biochemical findings in two cases of porphyria cutanea tarda (PCT) are presented. The cases are unique in their early age of onset (24 and 22 years) and their apparent precipitation by low-dosage oral contraceptives.Review of the literature reveals these to be the two youngest patients with estrogen-induced PCT. Only one other case of PCT induced by low-dosage oral contraceptives has been reported. In most cases of PCT induced by estrogens, high dosages have been taken by patients over age 35.     

Histological evidence of carcinoma in a hepatic tumour associated with oral contraceptives.

A primary hepatic tumour occurred in a 21-year-old woman who had been taking oral contraceptives for two years; she was treated by partial hepatectomy. Part of the neoplasm showed features suggestive of focal nodular hyperplasia, while the remainder had the histological characteristics of a well-differentiated hepatocellular carcinoma. This is the first report of malignant transformation of a tumour in a patient taking oral contraceptives.     

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

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.     

Effect of oral contraceptives on sebum excretion rate.

Oral contraceptives containing a high dose of oestrogen reduce the sebum excretion rate (SER) and improve acne vulgaris, but more progestogenic preparations may exacerbate acne. The effect on the SER of several oral contraceptives with varying progestogenic potencies was studied in 81 women. The predominantly progestogenic pills (Eugynon 30, Gynovlar) produced no significant change in SER, whereas the rate in women taking a more oestrogenic pill (Minovlar) was significantly reduced compared with the rate in controls. Progestogens therefore do not exacerbate acne by inducing seborrhoea, but in the doses we studied they nullified the inhibitory effect of oestrogens on the sebaceous glands. Acne-prone women who require an oral contraceptive should be given a predominantly oestrogenic preparation.     

Higher risk of venous thrombosis associated with drospirenone-containing oral contraceptives: a population-based cohort study

Background:

Combined oral contraceptives are a common method of contraception, but they carry a risk of venous and arterial thrombosis. We assessed whether use of drospirenone was associated with an increase in thrombotic risk relative to third-generation combined oral contraceptives.

Methods:

Using computerized records of the largest health care provider in Israel, we identified all women aged 12 to 50 years for whom combined oral contraceptives had been dispensed between Jan. 1, 2002, and Dec. 31, 2008. We followed the cohort until 2009. We used Poisson regression models to estimate the crude and adjusted rate ratios for risk factors for venous thrombotic events (specifically deep vein thrombosis and pulmonary embolism) and arterial thromboic events (specifically transient ischemic attack and cerebrovascular accident). We performed multivariable analyses to compare types of contraceptives, with adjustment for the various risk factors.

Results:

We identified a total of 1017 (0.24%) venous and arterial thrombotic events among 431 223 use episodes during 819 749 woman-years of follow-up (6.33 venous events and 6.10 arterial events per 10 000 woman-years). In a multivariable model, use of drospirenone carried an increased risk of venous thrombotic events, relative to both third-generation combined oral contraceptives (rate ratio [RR] 1.43, 95% confidence interval [CI] 1.15–1.78) and second-generation combined oral contraceptives (RR 1.65, 95% CI 1.02–2.65). There was no increase in the risk of arterial thrombosis with drospirenone.

Interpretation:

Use of drospirenone-containing oral contraceptives was associated with an increased risk of deep vein thrombosis and pulmonary embolism, but not transient ischemic attack or cerebrovascular attack, relative to second- and third-generation combined oral contraceptives.Oral hormonal therapy is the preferred method of contraception, especially among young women. In the United States in 2002, 12 million women were using “the pill.”¹ In a survey of households in Great Britain conducted in 2005 and 2006, one-quarter of women aged 16 to 49 years of age were using this form of contraception.² A large variety of combined oral contraceptive preparations are available, differing in terms of estrogen dose and in terms of the dose and type of the progestin component. Among preparations currently in use, the estrogen dose ranges from 15 to 35 μg, and the progestins are second-generation, third-generation or newer. The second-generation progestins (levonorgestrel and norgestrel), which are derivatives of testosterone, have differing degrees of androgenic and estrogenic activities. The structure of these agents was modified to reduce the androgenic activity, thus producing the third-generation progestins (desogestrel, gestodene and norgestimate). Newer progestins are chlormadinone acetate, a derivative of progesterone, and drospirenone, an analogue of the aldosterone antagonist spironolactone having antimineralo-corticoid and antiandrogenic activities. Drospirenone is promoted as causing less weight gain and edema than other forms of oral contraceptives, but few well-designed studies have compared the minor adverse effects of these drugs.³The use of oral contraceptives has been reported to confer an increased risk of venous and arterial thrombotic events,^4–7 specifically an absolute risk of venous thrombosis of 6.29 per 10 000 woman-years, compared with 3.01 per 10 000 woman-years among nonusers.⁸ It has long been accepted that there is a dose–response relationship between estrogen and the risk of venous thrombotic events. Reducing the estrogen dose from 50 μg to 20–30 μg has reduced the risk.⁹ Studies published since the mid-1990s have suggested a greater risk of venous thrombotic events with third-generation oral contraceptives than with second-generation formulations,^10–13 indicating that the risk is also progestin-dependent. The pathophysiological mechanism of the risk with different progestins is unknown. A twofold increase in the risk of arterial events (specifically ischemic stroke^6,14 and myocardial infarction⁷) has been observed in case–control studies for users of second-generation pills and possibly also third-generation preparations.^7,14Conflicting information is available regarding the risk of venous and arterial thrombotic events associated with drospirenone. An increased risk of venous thromboembolism, relative to second-generation pills, has been reported recently,^8,15,16 whereas two manufacturer-sponsored studies claimed no increase in risk.^17,18 In the study reported here, we investigated the risk of venous and arterial thrombotic events among users of various oral contraceptives in a large population-based cohort.