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.     

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.     

Studies of Carbohydrate and Lipid Metabolism in Women Developing Hypertension on Oral Contraceptives

Metabolic studies in 100 women developing hypertension on combined oestrogen-progestogen oral contraceptives have been compared with similar studies in normotensive women on oral contraceptives, matched for age and duration of contraceptive use, and in women not taking contraceptives.The metabolic changes known to be induced by oral contraceptives—impaired glucose tolerance, elevated blood pyruvate levels, and raised serum lipid concentrations—were found to be exaggerated in the matched hypertensive group, largely due to pronounced abnormalities in 33 subjects with diastolic blood pressures over 110 mm Hg.Women developing severe hypertension were older, more obese, and of higher parity than those with mild hypertension and there was a high incidence of previous toxaemia of pregnancy in the hypertensive group.The results show that in women on oral contraceptives changes in blood pressure and in metabolic functions tend to be correlated with one another, and are consistent with the hypothesis that oral contraception induces a primary biochemical effect whose expression in the individual is determined by intrinsic factors including genetic constitution, age, weight, and parity.     

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.     

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

     

血清PCT、CRP及内毒素在细菌性血流感染所致脓毒症患者中的早期诊断价值

目的:探究血清降钙素原(PCT)、C反应蛋白(CRP)及内毒素在革兰阳性(G+)杆菌与革兰阴性(G-)球菌血流感染所致脓毒症患者中的早期诊断价值。方法:回顾性分析2010年5月~2015年5月期间我院收治确诊的细菌性血流感染所致脓毒症患者123例,测定其血清PCT、CRP及内毒素水平,通过受试者工作特征曲线(ROC)曲线探究三者对细菌性血流感染所致脓毒症的评估价值。结果:血样培养结果显示,35例患者感染G+菌,88例患者感染G-菌;G-菌组患者血清PCT、CRP及内毒素水平均显著高于G+菌组(P0.05);且G+菌组、G-菌组及所有细菌组患者血清PCT、CRP、内毒素间均呈正相关关系(P0.05);ROC曲线显示,血清PCT、CRP和内毒素诊断G+菌血流感染所致脓毒症患者的截断值分别为1.58μg/L、95.25 mg/L与16.71ng/L,其灵敏度和特异度别为(65.92%,88.37%)、(67.39%,84.38%)与(56.34%,78.93%),诊断G-菌血流感染所致脓毒症患者的截断值分别为2.45μg/L、79.45 mg/L与15.54 ng/L,其灵敏度和特异度别为(78.73%,97.13%)、(68.89%,92.38%)与(65.39%,95.33%)。结论:检测血清PCT、CRP、内毒素水平有利于鉴别G-菌和G+菌血流感染所致脓毒症患者,且敏感度、特异度均较高,可用于早期诊断细菌性血流感染所致脓毒症。     

Proceedings: Correlation of various clinical parameters with glucose tolerance test in women using oral contraceptives

A study was carried out to determine whether oral contraceptives affect carbohydrate metabolism as assessed by glucose tolerance curves. Glucose tolerance tests were carried out in seventy-six women. The women were divided into two groups. The first group constituted the control and the second group comprised women taking combination oral contraceptives. The glucose tolerance curves were correlated with: (1) the duration of thereapy; (2) the family history of diabetes; (3) the obstetric history; (4) age: (5) weight gain; (6) parity; and (7) changes in blood pressure. The combination type of oral contraceptives were observed to affect adversely the glucose tolerance test. A significant correlation was recorded between the familial diabetic history, intake of combination contraceptives and abnormal glucose tolerance tests. A history of birth of a large baby was found to be an important indicator of abnormal values of glucose tolerance in women taking a combination type of oral contraceptive. Such women showed an abnormal curve pattern at a much earlier age in life compared with controls. It was also observed that a high percentage of women who had gained excessive weight on combination contraceptives had an altered glucose tolerance test. Parity and blood pressure were two parameters which did not reveal any correlation with abnormal glucose tolerance curves.     

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.     

Oral contraceptives and trisomy 21. A retrospective study of 730 cases (author's transl)]

A retrospective study of 730 cases of trisomy 21 and of 1 035 cases of abnormal children without a detectable chromosomal aberration, allows the study of the frequency of use of oral contraceptives by their mothers. The statistical analysis shows no notable differences for mothers 30 years old and younger. Among the mothers 30 to 38 years old, these is an excess of pill-taking by mothers of trisomy 21 children. For this second category of mothers (30 to 38 years) this excess is significant (a) when the delay between the cessation of pill-taking and the conception of the child is six months of less; (b) when the duration of pill-taking has been longer than one year; and (c), when those two factors are present simultaneously. Moreover, the frequency of males is significantly reduced in trisomy 21 children when their mothers have taken the pill. As a whole, for the subsample of mothers 30 and older, a correlation is observed between the three factors analysed, pill-taking, sex ratio, and trisomy 21. In view of the fact that decrease of the sex ratio and the increase of the frequency of trisomy 21 both are correlated with maternal aging in the general population, it seems remarkable that a correlation between these two variables and the use of oral contraceptives is observed only when the women had already passed the first of their reproduction period.     

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.     

Solitary liver nodules.

There has been confusion in the literature over the nomenclature of solitary liver nodules. Several such lesions have recently been reported in patients taking oral contraceptives. Similarities exist between these cases that suggest they may be examples of focal nodular hyperplasia. Here three further cases are presented. The criteria for making the diagnosis and its importance are discussed.     

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.     

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.     

Malignant hypertension in women of childbearing age and its relation to the contraceptive pill.

Eleven of 34 women aged 15-44 with malignant phase hypertension were taking oral contraceptives at presentation. All had had normal blood pressure before starting to take the pill. In four the interval between the start of oral contraception and the diagnosis of malignant hypertension was less than four months, and in eight no other cause for the hypertension was found. Underlying renal disease and renal failure were less common among pill users than among non-users with malignant hypertension who were of similar age. No pill user became normotensive after withdrawal of the pill, but blood pressure was well controlled (diastolic less than 90 mm Hg) in three patients taking only one drug. By contrast, all 23 non-users needed two or more antihypertensive drugs to control blood pressure. Ten year survival was 90% among pill users and 50% among non-users. These results suggest that oral contraceptives may be a common cause of malignant hypertension in women of child-bearing age. If the pill is stopped and underlying renal disease excluded the long term prognosis for such patients is excellent.     

Amenorrhoea after Discontinuing Combined Oestrogen-Progestogen Oral Contraceptives

Out of 210 women seen at the Middlesex Hospital with secondary amenorrhoea the 63 who developed it after stopping oral contraceptives were fully investigated. Five had organic disease sufficient to account for the amenorrhoea (one had severe diabetes, one a pituitary tumour, and three premature ovarian failure); two patients had galactorrhoea (one of whom also had the pituitary tumour); two had anorexia nervosa.Of the 63 women 40 (63%) had suffered from amenorrhoea or prolonged or irregular menstrual cycles before taking the pill, and this suggested that combined oestrogen-progestogen oral contraceptives should be used with caution for women with irregular menstruation.Nineteen patients wished to become pregnant and 12 have so far done so after treatment with clomiphene or gonadotrophins.In another study 204 women recorded when their first menstrual cycle occurred after stopping the pill. Seventy-four had a cycle longer than five weeks but only five exceeded three months, and only one of the five had more than six months'' amenorrhoea. These results confirm that the incidence of amenorrhoea after stopping oral contraceptives is low.     

Strokes among black people in Harare,Zimbabwe: results of computed tomography and associated risk factors.

Computed tomography was performed and risk factors evaluated in 100 consecutive adult patients presenting to the two teaching hospitals in Harare with a clinical diagnosis of stroke. The mean age of the patients was 52; only 28 were 65 or older. Non-stroke lesions were found in seven patients and were predicted by a recent history of convulsions (p less than 0.0001). Five lesions (four subdural haematomas and one cerebral cysticercosis) were remediable. Hypertension was present in 27 (93%) of the 29 patients with cerebral haemorrhage and in 49 (53%) of the 93 patients with stroke lesions. In 22 (45%) of these patients the hypertension had not been diagnosed, and another 22 had defaulted from treatment. All 13 patients who died before computed tomography had hypertension, and over half showed evidence of haemorrhagic stroke. There was a cardiac source for all 12 cases of cerebral embolism. In eight of the 100 patients cerebral infarction was attributed to neurosyphilis. None of the patients had clinical evidence of atherosclerosis. Smoking and oral contraceptives did not seem important risk factors for stroke. Detection and control of hypertension remain the most important measures needed to reduce the incidence of and mortality from stroke in Zimbabwe.     

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.     

Oral contraception and risk of a cerebral thromboembolic attack: results of a case-control study.

OBJECTIVE--To assess the risk of cerebral thromboembolism in women using low dose oral contraceptives. DESIGN--A retrospective case-control study. SETTING--All Danish medical, neurological, neurosurgical, and gynaecological departments. SUBJECTS--All 794 women in Denmark aged 15-44 who had suffered a cerebral thromboembolic attack during 1985-9 and 1588 age matched randomly selected controls. RESULTS--Of 692/1584 case/control questionnaires sent out, 590/1396 (85.3%/88.1%) were returned. Among the cases, 15 refused to participate, 69 had a revised or unreliable diagnosis, 40 had had thromboembolic disease previously, 13 were pregnant, and 152 had a disease predisposing to a cerebral thromboembolic attack. Of the 323 cases without a known predisposition, 320 reported use or non-use of oral contraception. Among the 1396 controls, eight refused to participate, were mentally retarded, or lived abroad; 18 returned an uncompleted questionnaire; 17 had had thromboembolic disease previously; 31 were pregnant; and 130 had a disease predisposing to a cerebral thromboembolic attack. Thus 1198 non-predisposed controls were available, among whom 1197 reported use or non-use of oral contraception. Among the 320 cases, 116 (36.3%) were oral contraceptive users at the time of the cerebral thromboembolic attack. By comparison there were 191 users (16.0%) among the 1197 controls, giving a crude odds ratio of 3.0. After multivariate analysis, including confounder control for age, smoking, years of schooling, and trend in use of different types of oral contraceptives during 1985-90, pills containing 50 micrograms oestrogen were associated with an odds ratio for cerebral thromboembolic attack of 2.9 (95% confidence interval 1.6 to 5.4), those containing 30-40 micrograms oestrogen an odds ratio of 1.8 (1.1 to 2.9), those containing progestogen only an odds ratio of 0.9 (0.4 to 2.4). The odds ratio did not change with increasing age or with duration of oral contraceptive use. A 50% increased risk of a cerebral thromboembolic attacks among cigarette smokers (after confounder control) was independent of oral contraception status and age. CONCLUSION--Low dose oral contraceptives are associated with an increased risk of cerebral thromboembolic attack. Combined or sequential pills containing 30-40 micrograms oestrogen are associated with a one third reduced risk compared with preparations containing 50 micrograms oestrogen. Progestogen only pills did not increase the risk of a cerebral thromboembolic attack.     

The return of the pharmaceutical industry to the market of contraception

In the 1980s and 1990s, the litigious climate in the US had a catastrophic effect on sales of many major contraceptives. Although oral contraceptives escaped controversy, the intrauterine device (IUD) and Norplant(R) were two targets of damaging litigation. The IUD was withdrawn from the market in 1985. Since 1994 when the attacks began against Norplant, its US sales have dramatically declined, even though no fault has been found in the method or its development. In general, pharmaceutical companies were extremely hesitant to develop new contraceptives during this period. The bleak outlook, however, began to shift in the late 1990s, as fertility rates began to decrease worldwide and contraceptive users increased. By 2025, 2500 million women will comprise the customer base for contraception. Global pharmaceutical companies are now participating in expanding markets overseas and have launched and continue to develop a range of new long-term reversible, and highly effective, contraceptive products outside the traditional oral contraceptive field. Two new contraceptives on the way to the US market are: Mirena, a levonorgestrel-releasing intrauterine system manufactured by Schering-Leiras; and Implanon, a single implant system manufactured by Organon of the Netherlands. Other birth control methods soon to be launched include: emergency contraceptives, the contraceptive patch, monthly contraceptive injections, mifepristone for medical abortion, and modified oral contraceptives.     

Steroid contraceptive use and pregnancy outcome

Contraceptive use in relation to pregnancy outcome was studied in 8,816 births in Chiang Mai, northern Thailand, by examination of newborn infants and interviews with their mothers. Four thousand twenty-three women used no contraception before the index pregnancy, 1,229 used the injectable contraceptive Depo Provera (DMPA), and 3,038 used oral contraceptives prior to or during pregnancy. No differences were observed between these groups with respect to still births, multiple pregnancies, and birthweight. Women who used oral contraceptives had unexpectedly low rates of major defects and may have been affected by self-selection bias, whereas the noncontraceptors had rates similar to other populations. There was a significantly increased association of polysyndactyly among infants of DMPA users relative to the other groups, which was most pronounced in offspring of women under age 30 years, and persisted after exclusion of subjects with a family history or infants with multiple abnormalities. However, in five out of the ten polysyndactyly cases, the last injection of DMPA occurred more than 9 months before conception, and only three cases had definite gestational exposure. The association of chromosomal anomalies was also significantly increased in infants of mothers who used DMPA. The unrelated nature of these defects, the lack of confirmation from other studies, the distant preconceptional exposure to DMPA in many cases, and chance effects due to multiple statistical comparisons make a causal association unlikely. Other birth defects that had been previously reported in some publications to be associated with progestational steroid exposure, such as neural tube defects, heart malformations, and limb reduction defects, were not found in this study.(ABSTRACT TRUNCATED AT 250 WORDS)