Oral contraception in 1983 (author's transl)

Recent studies have demonstrated new benefits of pill use, reduced risks associated with the minipill, and the possibility of screening out high risk women. The minipill is as effective as other formulations except in cases of chronic malnutrition or concomitant use of antibiotics or anticonvulsives. Oral contraceptives (OCs) frequently lessen menstrual problems. They prevent functional cysts in the ovaries, and reduce the incidence of benign breast tumors and the relative risk of developing ovarian cancer after 3 years of use. Combined OCs reduce the risk of endometrial cancer although sequentials increase it. OCs offer protection against salpingitis and other pelvic infections, against tubal pregnancies, and against chronic rheumatoid arthritis. Minipills appear to be less frequently associated with bothersome side effects than other OCs. The most significant risk of OCs is of death due to thrombo emboli of venous origin, myocardial ischemia, cerebrovascular accidents, and hypertension in women over 35, particularly those who smoke heavily. In 1981 the 2 British studies reported a reduced risk from these causes compared to results published in 1977. Estrogens are clearly responsible for some of the complications, apparently due to a weakening of the fibrinolytic systems, but progestagens or estrogen-progestagen combinations are also implicated. Arterial hypertension and cerebral and cardiac accidents appear to be due to the effect of progestagens on arterial tension, glucose metabolism, and the level of high density lipoprotein cholesterol. Risks of some liver diseases are elevated in pill users, but the question of tumors of the pituitary is not yet resolved. The incidence of uterine cancer appears to be elevated in pill users although the association is obscured by other factors. Some evidence exists of an association between estrogen-progestagen formulations and melanoma. No increase in abortion or fetal malformations except possibly an increase in twin pregnancies is noted after discontinuation of the pill. Pills should not be prescribed for smokers over 35 or any women over 45. Pills are possibly acceptable for women 35-44 in good health with no signs of diabetes, hypertension, or hyperlipoproteinemia. They should be followed up more frequently and should recognize the signs of complications.     

Oestrogen containing oral contraceptives decrease prostacyclin production (author's transl)

To study the production of antiaggregatory PGI2 (prostacyclin) the authors, observed 3 groups of women: 1) 34 women on combined OCs (oral contraceptives) for a period of 4 months--7 years; 2) 11 women starting contraception with progestogen only pills, or with low-dose estrogen pills; they were followed for a period of 3 months; and, 3) 24 women who had never been on OC. Blood samples were taken every month and examined. Results showed that: 1) the prolonged use of combined OCs was associated with decreased production of PG12, especially in relation to the length of OC treatment; 2) PG12 production was not affected by contraception with progestogens only; and, 3) no modifications were found in users of low-dose estrogen pills. The principal biological funcion of PG12 is to inhibit platelet aggregation, and to keep a proper dilatation of the blood vessels. Thus, suppression of PGI2 can be associated with an increased risk of venous and arterial thromboembolism in OC users. While the risk of thromboembolism may be decreased with low-dose estrogen treatment, risk of arterial thromoboembolism is not decreased, since OCs exercise a lesser influence on areterial thrombosis.     

Oral contraceptive pills and the risk of venous thromboembolism

Information on the association between combined oral contraceptives (OCs) and cardiovascular disease risks has been derived almost exclusively from studies in developed countries. To assess this relationship in developing countries, where the risk factors for cardiovascular disease may be different, a case-control study of venous thromboembolism, stroke, and myocardial infarction was carried out in 21 centers in 17 countries in Africa, Asia, Europe, and Latin America. The World Health Organization Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception enrolled 3800 cases of stroke, venous thromboembolism, and myocardial infarction and 11,200 matched controls. Studies in the UK had suggested that OCs containing desogestrel and gestodene doubled the risk of venous thromboembolism compared with levonorgestrel and norethindrone-containing OCs. The multi-center study identified an overall risk of venous thromboembolism in the lower range of that reported in developed countries, an increased risk soon after starting OC use but elimination of such risk within a few months after pill discontinuation, and slightly increased risk among obese women and those with a history of high blood pressure during pregnancy. Unexpected was the finding that women who use OCs containing desogestrel or gestodene may be at double the risk of blood clotting in the veins compared with users of OCs containing levonorgestrel or norethindrone. Although these findings remain controversial, several countries have modified OC prescribing practices to eliminate women at high risk of cardiovascular disease.     

Low-dose oral contraceptive-induced acute myocardial infarction

Objectives: Since their introduction, oral contraceptives (OCs) have been associated with risk to both the venous and the arterial systems. Studies have shown that OC use is associated with a risk of venous thromboembolism, ischaemic stroke and acute myocardial infarction (MI). MI is rarely seen in patients using OCs, particularly in the absence of clinical risk factors or smoking.

Case: We report a case of acute inferior MI in a 20-year-old non-smoker who had used a low-dose OC (3?mg drospirenone and 30?μg ethinyl estradiol) for 1 month. As far as we know, this is the youngest case of acute MI associated with a low-dose OC.

Conclusion: Low-dose OCs may also be responsible for acute MI even in a very young female without any cardiovascular risk factors. Therefore, the clinicians should be aware of this mortal events during follow-up of the patient using OCs.     

Third- and second-generation oral contraceptives are associated with similar risk estimates for venous thromboembolism

A scientific discussion between 1995 and 1999 addressed the question whether second- and third-generation oral contraceptives (OCs) were associated with different risks of venous thromboembolism (VTE). Results from three epidemiological studies became available in the course of 1995, in which such differences were observed. Although it was unclear at that time whether these observations reflected causality or were induced by bias and/or confounding, some regulatory bodies in Europe restricted the indication for use of third-generation oral contraceptives. Immediate media attention generated a pill scare in those, but also other, countries.

Indications for the influence of bias were observed in the initial studies of 1995 and further substantiated in subsequent utilization and prescribing surveys. The most important bias seemed to be related to differences in age and duration of use between third- and second-generation OC users. A number of new studies as well as new analyses in two of the 1995 databases included measures to limit the effect of the identified biases/confounders. These studies observed similar risks of venous thromboembolism with second- and third-generation oral contraceptives. Two other recently published studies did not or could not include the same level of control for confounding and reported similar results as the 1995 studies, thus reconfirming the relevance of the identified confounders. Population data show that the massive switch in the UK from third-generation OCs to second-generation OCs in 1995 has not resulted in a reduction of the incidence of VTE in OC users after 1995, illustrating that the risk of VTE is not determined by the type of low-dose pill used. In addition, data from trend analyses, spontaneous reporting and studies addressing hemostatic mechanisms in pill-users also do not support a potential difference in risk of VTE between users of second- and third-generation OCs.     

子宫腺肌病发生血栓性病变的风险及临床特点

子宫腺肌病（adenomyosis）是育龄期女性常见的良性疾病之一,主要临床表现为痛经、月经过多及不孕,严重影响患者的生活质量。近年来,国内外学者相继报道了30多例子宫腺肌病发生血栓性病变的病例,包括脑梗死、弥散性血管内凝血和静脉血栓栓塞症,这些病例多发生于月经期。分析这些患者的病变特点后发现,子宫腺肌病患者发生血栓性病变的危险因素包括炎症、组织因子表达增加、血糖类抗原125（CA125）水平升高、月经过多和子宫体积增大等。子宫腺肌病患者一旦发生血栓性病变,将增加临床上诊断和治疗的难度。了解子宫腺肌病患者凝血功能的变化和警惕其发生血栓性疾病的风险将有助于提高子宫腺肌病的诊疗准确率和安全性。     

Third generation progestagens

Although there is no epidemiologic proof, combined oral contraceptives (OCs) containing the derivatives of third generation progestins seem to bring patients better likelihood of favorable long-term performance and reduced risk of vascular events. These third generation progestins include desogestrel, gestodene, and norgestimate. Health workers must remember that this risk was no longer the same as that of the first statistics of the Royal College of General Practitioners which made one afraid of even the OCs with lower levels of ethinyl estradiol and first and second generation progestins. In either case, numerous studies proved the excellent clinical tolerance and acceptability of third generation progestins by patients. By reason of these qualities, women over 40 can probably continue to use them except if they have contraindications related to a personal or genetic condition. On the other hand, an already observed comparison has occurred between the third generation progestins, no matter whether they originated from progesterone or derivatives of nortestosterone. The first generation progestins were considered as exercising a progestenic and estrogen agonist effect and having excellent metabolic tolerance. While the second generation progestins were appreciated for their anti-gonadotropic properties and anti-estrogenic powers, their adverse metabolic effects were feared. Today, the latest norpregnane derivatives are also endowed with powerful anti-gonadotropic capacities whereas the recent derivatives of nortestosterone have lost a very big part of their metabolic weaknesses. Improvement of the lipid profile that they determine, in association with ethinyl estradiol, can bring hope that recent OCs can even contribute to the improvement of the arterial condition, at least in certain women. For example, women with a history of thromboembolism may be able to use the norpregnane derivatives, which are still under development.     

Oral contraceptives, thrombosis and haemostasis

The use of oral contraceptives is a well-established acquired risk factor for venous thrombosis. In 1995, a number of epidemiological studies were published which suggested that women who use third generation oral contraceptives that contain desogestrel or gestodene as progestagen are exposed to a two- to threefold higher risk for venous thrombosis than women using second generation oral contraceptives which contain levonorgestrel. In this paper, the effects of oral contraceptives on the haemostatic system are discussed. It appears that plasma from oral contraceptive users is resistant to the anticoagulant action of activated protein C (APC). This phenomenon, called acquired APC resistance, is more pronounced in users of desogestrel or gestodene-containing oral contraceptives than in women who use oral contraceptive pills with levonorgestrel. On the basis of these observations, it was proposed that acquired APC resistance may be the mechanistic basis of the increased risk for venous thrombosis during oral contraceptive use and for the further increased thrombotic risk of third generation oral contraceptive users. Furthermore, the results of a recent cross-over study are discussed. This study indicated that a large number of other haemostatic parameters were changed during oral contraceptive use. Some of these changes were more pronounced on desogestrel-containing oral contraceptives. The cross-over study also showed that the increased fibrinolytic activity during OC use is counterbalanced by an enhanced activity of thrombin-activatable fibrinolysis inhibitor (TAFI), a protein that participates in the inhibition of fibrinolysis.     

Oral progestogen-only contraceptives and cardiovascular risk: results from the Transnational Study on Oral Contraceptives and the Health of Young Women.

BACKGROUND: The risk of cardiovascular disease associated with progestogen-only pills has rarely been studied so far. METHODS: In the Transnational case-control study we were looking for a potential cardiovascular disease risk with oral progestogen-only pills in women aged 16-44 years. A total of 1058 cases of myocardial infarction, thromboembolic cerebrovascular accident or venous thromboembolism, and 3808 controls unaffected by these diseases, were enrolled. The group of women who had either used oral progestogen-only pills or no oral contraceptives included 394 cardiovascular disease cases (123 cases of myocardial infarction, 90 cases of thromboembolic cerebrovascular accident and 181 cases of venous thromboembolism) and 2366 controls. RESULTS: The adjusted (matched) odds ratio (OR) for all cardiovascular diseases combined for women using progestogen-only pills compared with non-users of oral contraceptives was 0.84 (95% confidence interval (CI), 0.45-1.58). The adjusted ORs for myocardial infarction, thromboembolic cerebrovascular accidents and venous thromboembolism for users of progestogen-only pills were 0.94 (95% CI, 0.31-2.91), 1.60 (95% CI, 0.24-0.72) and 0.68 (95% CI, 0.28-1.66), respectively. Hence, there was no significant increase in cardiovascular disease risk associated with progestogen-only pill use. The association between cardiovascular disease and established risk factors (smoking and hypertension) was confirmed. CONCLUSION: Although limited by the small number of exposed cases, our data suggest that there is no convincing evidence for an increased risk of cardiovascular disease associated with progestogen-only pill use.     

Hepatic complications of oral contraceptives

By 1977, with 54 million women using oral contraceptives (OCs), various hepatic complications of their use were being suggested. The majority of women suffering complications used high-dose formulations of combination pills, and the low-dose preparations have not been in use long enough for their effects to be known. Subclinical modifications of liver tests were the most common and the least serious effects reported; they disappeared with cessation of treatment, and were in proportion to the strength of the dose. Transaminases and alkaline phosphatases are currently almost always normal. Despite causing a reduction of biliary excretion, OCs seldom provoke jaundice; normal livers have a large reserve excretory capacity. OC related jaundice usually appears within the 1st 6 months of pill use and disappears without sequelae 1 or 2 months after termination of pill use. 50% of women developing jaundice with pill use had experienced intrahepatic cholestasis of pregnancy. OCs are thus contraindicated for women experiencing cholestasis of pregnancy as well as those experiencing any kind of chronic cholestasis. Women taking OCs almost always have elevated cholesterol levels in their bile, which probably explains the increased frequency of cholecystectomies for vesicular lithiase in women taking OCs or estrogens. Anomalies in the composition of bile almost always disappear when OC use is stopped. The role of OCs in the development of hepatic adenomas was discovered through epidemiologic methods. The danger of these benign tumors is related to the risk of a hemoperitoneum or intratumoral bleeding. Pill use should be stopped if such a tumor is discovered, the tumor should be monitored, and surgery may be performed in the case of a large growth. Focal nodular hyperplasias are less dangerous than hepatic adenomas but still necessitate stopping pill use. They have been observed in men and children and were reported in women prior to widespread use of the pill, but OC use appears to favor their growth and the development of complications. Cases of hepatocellular carcinoma in women using pills appear to be due to coincidence. OCs appear very likely to be involved in the development of subhepatic vein thrombosis or the Budd-Chiari syndrome, due primarily to their estrogen content. Pill use should be stopped if these conditions arise.     

Metrorrhagia caused by estrogen-progestin combinations

Changes in combined oral contraceptives (OCs) include reduction in the estrogen and progestogen dose and recourse to the third generation, less androgenic progestogens. They retain the efficacy and convenience of OCs while reducing the metabolic and cardiovascular effects and the need to identify contraindications and subjects at risk. OCs sometimes cause menstrual cycle problems: spotting and intercurrent bleeding or bleeding at any time other than menstruation (metrorrhagia). OCs cause loose and edematous stroma in the endometrium where glands maintain a proliferative-like phase throughout the cycle. Many dilated capillaries with hyperplasia of the endothelial cells rise to the surface. Forgetting or failure to take OC pills are often responsible for intercurrent bleeding. It is hard to determine what OCs cause less bleeding than other OCs. The third generation progestogen, gestodene, appears to have better cycle control than the two other third generation progestogens (desogestrel and norgestimate). It is not clear whether triphasic OCs with second generation progestogens are better than monophasic third generation OCs. The OC with low dose ethinyl estradiol (20 mcg) (Mercilon) has as low a bleeding rate as does the OC, Varnoline (30 mcg). Menstrual cycle disturbances rarely happen. Providers must emphasize to new OC users the possibility of spotting or intercurrent bleeding, especially during the first cycle. Providers must also inform them that these disturbances do not affect the effectiveness of the OCs and that they should not stop taking OCs if they are concerned about bleeding. Providers must instruct them what to do if they forget to take a pill(s). Providers should schedule an appointment after a new OC user has completed the third OC packet. They should do a gynecologic exam to search for a genital infection, endo-uterine polyp or fibroma, and hyperplasia of the endometrium. If bleeding persists during the third cycle, the client should change contraception.     

Oral Contraceptive Use and the Cardiovascular Health of Canadian Women

Objectives: to review the published literature on the association between oral contraceptive (OC) use and cardiovascular disease, in particular venous thromboembolism (VTE) and acute myocardial infarction (AMI). To determine if there is an increased risk for VTE due to the use of the new progestins. To use the results of the analysis to construct a Canadian model.Methods: meta-regression was used to analyze adjusted relative risks from 18 studies for VTE and from 15 studies for AMI. The resulting risks were applied to the Canadian population of OC users, to calculate event and mortality rates for both, second and third generation progestin use.Results: the relative risk of VTE with the use of OCs consisting of low dose ethinyl estradiol (EE) with new progestins was 7.7 and with other progestins was 3.5, compared with non-use. The relative risk of AMI with new progestins was 1.2 and with other progestins was 2.9. In the Canadian model, there were 25 VTE and two AMI events annually/100,000 women for users of OCs with new progestins, and 11 VTE and four AMI events for users of OCs with other progestins, compared to three VTE and two AMI events for similar non-users. The exclusive use of OCs with new progestins potentially would decrease by seven the annual number of OC-attributable cardiovascular deaths in Canada.Conclusions: the published results appear to exaggerate both the VTE risk and the AMI benefit associated with the new progestins, because of bias including differences in the duration of use. Oral contraceptives should be avoided by women with other risk factors for cardiovascular disease; however, the typical OC user should not avoid or choose an OC based on the extremely small shifts in the cardiovascular risks between VTE and AMI.     

Right neck venous thrombosis following ovarian hyperstimulation syndrome in a patient with protein S deficiency: A case report and review of literature

ObjectiveThe risk of venous thromboembolism in pregnancies increased in ovarian hyperstimulation syndrome (OHSS) after assisted reproductive technologies (ART). We present a rare case with protein S deficiency receiving ART treatment with OHSS, following right neck venous thromboembolism.Case reportA 34-year-old women with primary infertility underwent IVF treatment and presented with OHSS. However, thromboembolism in the right jugular and subclavian veins was diagnosed at eight weeks of gestation. She was continuously treated with low molecular weight heparin (LMWH) since eight weeks of gestation and the diagnosis of protein S deficiency was made. Due to placenta previa with massive bleeding, she gave live birth to two healthy babies via cesarean section at 34 weeks of gestation.ConclusionThromboembolism is one of life-threatening complications among women with OHSS. Although inherited thrombophilia is rare diseases, thrombophilia workup may be taken into consideration for women with thrombotic events.     

Presence of the "Beaumont" protein in serum of oral contraceptive users

The level of the "Beaumont" protein present in serum was measured by a population of 223 black and 76 Caucasian women with different exposures to oral contraceptives (OCs). No differences were found in the values in nonusers, past users, current users, or new users of OCs. The values were higher in black nonusers and users than in comparable Caucasian groups, suggesting a racial difference. A group of 55 thrombotic women were subclassified by type of thrombosis and exposure to OC therapy. No significant difference was seen between the values in thrombotic women exposed or not exposed to OCs. A similar result was obtained when the types of thrombosis (arterial or venous) were compared. These results do not confirm Beaumont's hypothesis that antibodies are induced by contraceptive steroids in a subgroup of women on OC therapy.     

Anticoagulants

Pregnancy is a period of heightened coagulability and enhanced risk for thrombotic complications. Thromboembolism is the leading cause of maternal mortality. Anticoagulants are very useful during pregnancy for the acute treatment of venous thromboembolism and for the prevention of recurrent venous thromboembolism. They may also be beneficial in patients with thrombophilias, particularly among women who have experienced adverse pregnancy outcomes such as recurrent pregnancy loss. Anticoagulation is essential but problematic in the management of pregnant women with mechanical heart valve prostheses. When utilizing these medications among pregnant women the potential benefits must be balanced against the possibility of maternal haemorrhagic complications, adverse effects on the pregnancy or toxic effects on the fetus. This chapter summarizes current knowledge about the anticoagulant agents, their potential toxicities and their therapeutic role in pregnant women with various indications for anticoagulant therapy.     

Practice bulletin no. 123: thromboembolism in pregnancy

Pregnant women have a fourfold to fivefold increased risk of thromboembolism compared with nonpregnant women (1, 2). Approximately 80% of thromboembolic events in pregnancy are venous (3), with a prevalence of 0.5–2.0 per 1,000 pregnant women (4–9). Venous thromboembolism, including pulmonary embolism, accounts for 1.1 deaths per 100,000 deliveries (3), or 9 % of all maternal deaths in the United States (10). In the developing world, the leading cause of maternal death is hemorrhage (11); however, in developed nations, where hemorrhage is more often successfully treated and prevented, thromboembolic disease is one of the leading causes of death (12). The prevalence and severity of this condition during pregnancy and the peripartum period warrant special consideration of management and therapy. Such therapy includes the treatment of acute thrombotic events and prophylaxis for those at increased risk of thrombotic events. The purpose of this document is to provide information regarding the risk factors, diagnosis, management, and prevention of thromboembolism, particularly venous thromboembolism in pregnancy.