Dissecção espontânea da artéria coronária, uma doença multifatorial: perspectivas da experiência de um centro / Spontaneous coronary artery dissection, a multifactorial disease: insights from a center experience

Introdução: Embora seja uma doença pouco conhecida, a dissecção espontânea da artéria coronária é uma causa importante e frequentemente subdiagnosticada da síndrome coronariana aguda não aterosclerótica, principalmente em mulheres. O objetivo deste estudo foi caracterizar uma amostra consecutiva de pacientes diagnosticados com dissecção espontânea da artéria coronária quanto a fatores predisponentes e desencadeadores; quadro clínico e angiográfico; abordagem terapêutica; ocorrência de eventos cardíacos adversos; recorrência e dissecção espontânea de artéria coronária de novo. Métodos: Estudo retrospectivo observacional longitudinal, unicêntrico, que incluiu pacientes diagnosticados com dissecção espontânea da artéria coronária (n=60) admitidos entre janeiro de 2010 e dezembro de 2020. Resultados: A mediana da idade foi de 55 anos, e 83% eram mulheres. A maioria dos pacientes (60%) não apresentava nenhum ou tinha apenas um fator de risco cardiovascular. O infarto agudo do miocárdio sem supradesnivelamento do segmento ST foi o quadro clínico em 67% dos casos. A artéria coronária mais frequentemente envolvida foi a descendente anterior (47%). A maioria das lesões (77%) aparecia na angiografia como dissecção espontânea da artéria coronária tipo 2. O tratamento conservador foi selecionado como abordagem inicial na maioria dos pacientes (72%). A incidência geral de dissecção espontânea da artéria coronária de novo não foi significativamente diferente entre os pacientes tratados primeiramente com revascularização, em comparação com os que receberam tratamento conservador (p=0,953). No entanto, a recidiva da dissecção espontânea da artéria coronária ocorreu no vaso originalmente envolvido em 3 dos 15 pacientes tratados com revascularização, em comparação com apenas um entre os 43 pacientes que foram tratados de forma conservadora (p<0,05). Conclusão: A dissecção espontânea da artéria coronária é mais frequente em mulheres jovens. O infarto agudo do miocárdio sem supradesnivelamento do segmento ST foi o quadro clínico mais observado, envolvendo principalmente a artéria descendente anterior. A revascularização não protegeu da recorrência.

Background: Although it is a poorly known disease, spontaneous coronary artery dissection is an important and frequently underdiagnosed cause of non-atherosclerotic acute coronary syndrome, particularly in women. The objective of this study was to characterize a consecutive sample of patients diagnosed with spontaneous coronary artery dissection with respect to predisposing and precipitating factors; clinical and angiographic presentation; management; occurrence of adverse cardiac events; recurrence; and de novo spontaneous coronary artery dissection. Methods: Longitudinal, observational, retrospective, single-centre study, including patients diagnosed with spontaneous coronary artery dissection (n=60) admitted between January 2010 and December 2020. Results: Median age was 55 years, and 83% were women. Most patients (60%) presented without any or just one cardiovascular risk factor. Non-ST-segment elevation acute myocardial infarction accounted for 67% of clinical presentations. The most frequently affected coronary artery was the left anterior descending (47%). Most lesions (77%) appeared on angiography as type 2 spontaneous coronary artery dissection. Conservative management was chosen as the initial approach in most patients (72%). The overall incidence of de novo spontaneous coronary artery dissection was not significantly different among patients initially managed with revascularization as compared to conservative treatment (p=0.953). However, spontaneous coronary artery dissection recurrence occurred in the originally involved vessel in 3 of 15 patients initially managed with revascularization, as compared to only one among 43 patients treated conservatively (p<0.05). Conclusion: Spontaneous coronary artery dissection occurs more often in young women. Non- ST-segment elevation acute myocardial infarction was the most frequent clinical presentation involving mainly the left anterior descending artery. Revascularization did not protect from recurrence.

Cardiovascular disease: pathogenesis, epidemiology, and risk among users of oral contraceptives who smoke.

Smoking increases the risk of lung cancer and cardiovascular disease among persons of both sexes. The risk of cardiovascular disease is further increased among users of oral contraceptives who smoke, particularly those who are >/=35 years old or carry the coagulation factor V Leiden mutation. Other important cardiovascular disease risk factors in women include waist/hip girth ratio >0.8, high concentration of low-density lipoprotein cholesterol (>115 mg/dL), high triglyceride level (>/=150 mg/dL) with low concentration of high-density lipoprotein cholesterol (/=100 mg/dL, hypertension, lack of physical activity, and high-fat diet. Most excess cardiovascular disease among users of oral contraceptives is due to thrombosis (not atherosclerosis); studies indicate that the lower the oral contraceptive estrogen dose is, the lower is this risk. Oral contraceptives containing the third-generation progestins desogestrel and gestodene have been associated with greater risks of venous thromboembolism than are associated with older progestins, although there is some controversy surrounding these findings.

PIP: This paper examines the pathogenesis, epidemiology and risk of cardiovascular disease due to smoking and oral contraceptive (OC) use among women. The major risks associated with smoking were cardiovascular diseases and lung cancer. Characteristics of a syndrome which significantly increases the cardiovascular disease risk include: waist/hip girth ratio 0.8, glucose concentration 100 mg/dl, insulin 25 mU/l, peptide C 1.3 nmol/l, blood pressure 135/85 mm Hg, high triglyceride level 150 mg/dl with low concentration of HDL cholesterol (45 mg/d), total cholesterol/HDL ratio 4.0, LDL cholesterol (small dense pattern B) 130 mg/dl, uric acid concentration 7 mg/dl, and microalbuminuria 30-200 mg/dl. Women users over age 35 carrying the coagulation factor V Leiden mutation were found to be at increased risk of death from cardiovascular disease. The study indicates that increasing the estrogen dosage in an OC from 20 to 50 mcg ethinyl estradiol produced greater risks. Most cardiovascular disease among OC users is due to thrombosis. OCs containing the third-generation progestins desogestrel and gestodene have been associated with greater risks of venous thromboembolism that are associated with older progestins, although there is some controversy surrounding these findings. Smokers must be discouraged. When middle-aged women stopped smoking, about a third of their excess risk for coronary heart disease was eliminated within 2 years of cessation, and their risk became similar to that of nonsmoking women within 10-14 years.

Smoking and use of oral contraceptives: impact on thrombotic diseases.

OBJECTIVES: The study was intended to evaluate the effects of oral contraceptives and smoking on the risks of arterial and venous thromboembolic diseases among young women. STUDY DESIGN: The study included a survey of data from published epidemiologic studies and evaluation of registry records of all Danish women discharged from the hospital from 1980 through 1993 after a first thromboembolic event. Questionnaires returned by survivors of such events and by control women during the period from 1994 through 1995 were analyzed. RESULTS: In the 1980-1993 data the absolute risk of thrombotic diseases was seen to increase rapidly with age-exponentially for acute myocardial infarction or cerebral thromboembolic attack, linearly for venous thromboembolism-with risks of arterial diseases exceeding those of venous diseases. In the 1994-1995 data the relative risk of thrombotic diseases was seen to increase among users of oral contraceptives irrespective of age. Risk of venous thromboembolism (but not of acute myocardial infarction or cerebral thromboembolic attack) declined as duration of current oral contraceptive use lengthened, risk of acute myocardial infarction or cerebral thromboembolic attack was significantly decreased as ethinyl estradiol doses were reduced, and the relative risk (compared with nonusers of oral contraceptives) for arterial thromboembolic disease among users of desogestrel or gestodene (in conjunction with midrange or low doses of ethinyl estradiol) was lower than the relative risk among users of second-generation progestogens (in conjunction with midrange doses of ethinyl estradiol). The combination of smoking with oral contraceptive use may have a synergistic effect on risks of acute myocardial infarction and cerebral thromboembolic attack (but not of venous thromboembolism), particularly among users of high-dose (50 micrograms) ethinyl estradiol preparations. CONCLUSION: Among the formulations currently marketed in Denmark, where only the progestins desogestrel and gestodene are available with low-dose (20 micrograms) ethinyl estradiol (and only desogestrel was available in that form at the time of our studies), we prefer these third-generation oral contraceptives for smokers. We might also consider such oral contraceptives for women >35 years old as long as they had no other risk factors for thrombotic arterial diseases.

PIP: This study assesses the effects of cigarette smoking and oral contraceptive (OC) use on the risks of arterial and venous thromboembolic diseases among women in their reproductive years. A survey of published epidemiologic studies is included together with an evaluation of registry records of Danish women discharged from hospitals from 1980 through 1993 after a first thromboembolic event. Analysis was made of questionnaires sent to survivors of such an event and to control women during the period from 1994 through 1995. The study also includes an evaluation of thrombotic disease prevalence, determination of OC influence on the risk of the disease, and comparison of disease prevalence among smoking and nonsmoking users of OC. Results showed that the risk of acute myocardial infarction among OC users was significantly higher than among non-OC users. OC use had less of an effect on acute myocardial infarction risk than on the risk of cerebral thromboembolic attack. The risk of venous thromboembolism among users of OC was influenced by the duration of OC use; the shorter the use, the higher the risk, while smoking had little effect. Epidemiologic studies suggest that arterial disease risk in young (men/women) decreases within 5-10 years of smoking cessation. Smoking, with a low dose of OC, acted as an independent risk factor for myocardial infarction and cerebral attack. The absolute risk for older nonusers and nonsmokers was higher by 10-fold than the risk for younger counterparts. Thus, among the formulations available in Denmark, preference is given to third-generation OCs for young female smokers and for smoking women over age 35, provided they have no other risk factor for thrombotic arterial disease.

Oral contraceptives and myocardial infarction: results of the MICA case-control study.

OBJECTIVES: To determine the association between myocardial infarction and use of different types of oral contraception in young women. DESIGN: Community based case-control study. Data from interviews and general practice records. SETTING: England, Scotland, and Wales. PARTICIPANTS: Cases (n=448) were recruited from women aged between 16 and 44 who had suffered an incident myocardial infarction between 1 October 1993 and 16 October 1995. Controls (n=1728) were women without a diagnosis of myocardial infarction matched for age and general practice. MAIN OUTCOME MEASURES: Odds ratios for myocardial infarction in current users of all combined oral contraceptives stratified by their progestagen content compared with non-users; current users of third generation versus second generation oral contraceptives. RESULTS: The adjusted odds ratio for myocardial infarction was 1.40 (95% confidence interval 0.78 to 2. 52) for all combined oral contraceptive users, 1.10 (0.52 to 2.30) for second generation users, and 1.96 (0.87 to 4.39) for third generation users. Subgroup analysis by progestagen content did not show any significant difference from 1, and there was no effect of duration of use. The adjusted odds ratio for third generation users versus second generation users was 1.78 (0.66 to 4.83). 87% of cases were not exposed to an oral contraceptive, and 88% had clinical cardiovascular risk factors or were smokers, or both. Smoking was strongly associated with myocardial infarction: adjusted odds ratio 12.5 (7.29 to 21.5) for smoking 20 or more cigarettes a day. CONCLUSIONS: There was no significant association between the use of oral contraceptives and myocardial infarction. The modest and non-significant point estimates for this association have wide confidence intervals. There was no significant difference between second and third generation products.

PIP: The association between myocardial infarction and use of oral contraceptives (OCs) was investigated in a case-control study conducted in England, Scotland, and Wales. 448 women 16-44 years old who had suffered an incident myocardial infarction during 1991-95 were identified from general practice records and matched by age and general practice with 1728 healthy controls. 85% of cases were not taking OCs in the 3 months before their myocardial infarction. The adjusted odds ratio (OR) for myocardial infarction was 1.40 (95% confidence interval [CI], 0.78-2.52) for all combined OC users, 1.10 (95% CI, 0.52-2.30) for users of second-generation formulations, and 1.96 (95% CI, 0.87-4.39) for third-generation OCs. Subgroup analysis by progestogen content did not show any significant difference from 1, and there was no effect of duration of OC use. 88% of cases had clinical cardiovascular risk factors or were smokers, or both. The adjusted OR for third-generation vs. second-generation OC users was 1.78 (95% CI, 0.66-4.83). The adjusted OR was 12.5 (95% CI, 7.29-21.5) among women who smoked 20 or more cigarettes a day. These findings indicate that OCs, including third-generation formulations, do not increase a woman's risk of myocardial infarction. Women who are concerned about their cardiovascular health should be urged to stop smoking, however.

Forearm bone density in users of Depo-Provera as a contraceptive method.

OBJECTIVE: To determine the influence of depot medroxyprogesterone acetate (MPA) on bone mineral density when used as a contraceptive method. DESIGN: Cross-sectional study. SETTING: Academic tertiary-care hospital. PATIENT(S): Fifty premenopausal women who had used depot MPA as a contraceptive method for > or =1 year and 50 women who had never used hormonal contraceptive methods. INTERVENTION(S): Bone mineral density was evaluated at the midshaft and at the distal radius of the nondominant forearm using single x-ray absorptiometry. MAIN OUTCOME MEASURE(S): Bone mineral density. RESULT(S): Bone mineral density at the midshaft of the forearm was lower in depot MPA users than in women who had never used hormonal contraceptive methods, but the difference was not statistically significant. At the distal portion, bone mineral density was significantly lower in the study group. The duration of depot MPA use was not related to bone mineral density. CONCLUSION(S): Women > or =35 years of age presented with a lower bone mineral density only at the distal portion of the forearm after the use of depot MPA for > or =1 year. However, this decrease was not related to the duration of depot MPA use. It is not possible to conclude that women who use depot MPA are at risk of osteoporosis.

PIP: The impact of depot medroxyprogesterone acetate use on bone mineral density was assessed in a cross-sectional study of 100 women recruited from a teaching hospital in Campinas, Brazil, during 1996-98. Bone mineral density, as evaluated at the midshaft and distal radius of the nondominant forearm by single x-ray absorptiometry, was compared in 50 women 35-45 years of age who had been using Depo-Provera for contraception for 1 year or more (mean duration, 46.4 +or- 38.6 months) but had never used any other hormonal method and 50 age- and weight-matched women who had never used any form of hormonal contraception. Although mean bone mineral density at the midshaft of the forearm was lower in Depo-Provera users than nonusers of hormonal contraception (0.459 +or- 0.042 vs. 0.474 +or- 0.049 g/sq. cm), the difference was not statistically significant. At the distal portion, bone mineral density was significantly lower in Depo-Provera users than nonusers of hormonal methods (0.362 +or- 0.040 vs. 0.392 +or- 0.049 g/sq. cm, p 0.001). The duration of Depo-Provera use was not related to bone mineral density, even when women had used the method for more than 5 years. Multiple regression analysis indicated that 4 pregnancies, White race, and Depo-Provera use were significantly associated with lower bone mineral density at the midshaft section of the forearm; at the distal section of the forearm, these variables were Depo-Provera use, more than 4 pregnancies, White race, older age at menarche, and habitual coffee drinking. These findings do not provide sufficient evidence to conclude that Depo-Provera users are at increased risk of osteoporosis.

Breast cancer risk: perception versus reality.

Evidence that breast cancer is hormonally mediated has fueled women's concern that use of oral contraceptives (OC) will increase their risk of developing the disease. A recent reanalysis of combined worldwide epidemiologic evidence regarding the relationship between breast cancer risk and use of combination OC provides reassurance that there is little or no association between OC use and breast cancer. Ten or more years after discontinuation of OC use, there is no difference in cumulative risk of breast cancer among OC ever-users and never-users. The risk of breast cancer diagnosis is slightly elevated in current OC users and remains slightly elevated until about 10 years after OC discontinuation. Once recency of use is taken into account, other characteristics have little additional effect. There is no increase in breast cancer risk with increasing dose or duration of OC use and no difference in risk related to type of estrogen or progestin used. Moreover, those breast cancers diagnosed in OC ever-users were found to be significantly more likely to be localized than those diagnosed in same-age never-users.

PIP: A recent survey of US women 40-50 years old with no history of breast cancer found that women's perceptions of their risk of developing and dying of breast cancer exceeded the actual risk. Evidence that breast cancer is hormonally mediated has raised concerns that oral contraceptive (OC) use increases a woman's risk of developing the disease. This concern has been fueled by the observation that the increasing diagnosis of breast cancer in many countries has occurred in tandem with widespread OC use. However, a reanalysis by the UK Imperial Cancer Research Fund Epidemiology Unit of worldwide epidemiologic data revealed little or no evidence of a link between OC use and breast cancer. 10 or more years after discontinuation of OCs, there is no difference in cumulative breast cancer risk between OC ever-users and nonusers. Breast cancer risk among ever-users was not affected by duration of OC use, age at first use, parity, family history, or the dose or type of OC. Moreover, breast cancers diagnosed in OC ever-users are significantly less advanced and more likely to be localized to the breast than those in never-users. It may be that current or recent OC users are receiving more breast examinations and therefore have the opportunity for early diagnosis and improved prognosis.

Contraceptive failure, method-related discontinuation and resumption of use: results from the 1995 National Survey of Family Growth.

CONTEXT: Half of all pregnancies in the United States are unintended. Of these, half occur to women who were practicing contraception in the month they conceived, and others occur when couples stop use because they find their method difficult or inconvenient to use. METHODS: Data from the 1995 National Survey of Family Growth were used to compute life-table probabilities of contraceptive failure for reversible methods of contraception, discontinuation of use for a method-related reason and resumption of contraceptive use. RESULTS: Within one year of starting to use a reversible method of contraception, 9% of women experience a contraceptive failure--7% of those using the pill, 9% of those relying on the male condom and 19% of those practicing withdrawal. During a lifetime of use of reversible methods, the typical woman will experience 1.8 contraceptive failures. Overall, 31% of women discontinue use of a reversible contraceptive for a method-related reason within six months of starting use, and 44% do so within 12 months; however, 68% resume use of a method within one month and 76% do so within three months. Multivariate analyses show that the risk of contraceptive failure is elevated among low-income women and Hispanic women. Low-income women are also less likely than other women to resume contraceptive use after discontinuation. CONCLUSIONS: The risks of pregnancy during typical use of reversible methods of contraception are considerably higher than risks of failure during clinical trials, reflecting imperfect use of these methods rather than lack of inherent efficacy. High rates of method-related discontinuation probably reflect dissatisfaction with available methods.

PIP: This study computed life table probabilities of contraceptive failure, discontinuation of use, and return to contraceptive use in the US. Data were obtained from the 1995 National Survey of Family Growth (NSFG) among a nationally representative sample of 6867 contraceptive use intervals contributed by women 15-45 years old who began use or resumed use after discontinuation during 1991-95. Analysis was based on Kaplan-Meier product-limit single decrement life table probability methods. Findings indicate that the risk of failure during typical use of reversible methods was 9% within 1 year of starting. Women with continuous lifetime use will experience 1.8 contraceptive failures. Failure rates were 7% for the pill, 9% for the male condom, 8% for the diaphragm, 20% for periodic abstinence, and 15% for spermicides. Failure rates reflect imperfect use. 31% of women discontinued use within 6 months of starting use. 44% discontinued within 12 months. Women using reversible methods continuously will discontinue use nearly 10 times during the reproductive period. Most women resumed use shortly after discontinuation. Low income women had higher risk of unintended pregnancy for all methods and the pill and lower risk of resumption after discontinuation. Hispanics had a higher risk of contraceptive failure for all methods and the condom. Black women had a higher risk of discontinuation of oral pills and condoms.

Measuring contraceptive use patterns among teenage and adult women.

CONTEXT: Measures of contraceptive use at one point in time do not account for its changing nature. A measure that addresses the pattern of method use over time may better predict the cumulative risk of unintended pregnancy. METHODS: Women at risk of unintended pregnancy were selected from the 1995 National Survey of Family Growth, and their contraceptive use patterns were compared across age-groups. Survival analysis was used to validate women's long-term use pattern as an indicator of pregnancy risk, and multivariate regression analyses were used to explore potential covariates of current patterns of contraceptive use. RESULTS: More than two-thirds of women aged 15-19 report long-term uninterrupted contraceptive use, but they are more likely to report sporadic use and less likely to report uninterrupted use of a very effective method than are women aged 25-34. Compared with women aged 25-34, women aged 20-24 have higher rates of sporadic use and lower rates of effective uninterrupted use. Among teenagers, nonusers are 12 times as likely as uninterrupted effective users to experience an unintended pregnancy within 12 months at risk. Women in less stable relationships, those having more infrequent intercourse and women who have recently experienced nonvoluntary intercourse for the first time are more likely than others to have a high-risk contraceptive pattern. Women aged 17 and younger whose current partner is more than three years older are significantly less likely to practice contraception than are their peers whose partner is closer in age. CONCLUSIONS: Long-term contraceptive use pattern is a valid predictor of unintended pregnancy risk. Policies aimed at reducing unintended pregnancies should target women who do not practice contraception and those who are sporadic users. Women in unstable relationships, those having infrequent sex and women who experience sexual coercion need access to methods, such as emergency contraception, that can be used sporadically or after unprotected intercourse.

PIP: This study examined determinants of unintended pregnancy in the US. Data were obtained from the 1995 National Survey of Family Growth among 7221 women 15-44 years old at risk of unintended pregnancy. Findings indicate that adolescents were not mainly sporadic method users in 1995. Most used a method without interruption for an extended period. Teenagers were more likely to report sporadic contraceptive use and were less likely to be uninterrupted users of effective methods. Women 20-24 years old were no more likely than 18-19 year old women to report long-term sporadic use and were more likely than women 25-34 years old to report long-term sporadic use. Nonusers and sporadic users contributed significantly to the high rate of unintended pregnancies. Logistic models reveal that women who were married or cohabiting were more likely to be uninterrupted effective contraceptive users than those not in long-term relationships. Frequency of intercourse had a consistent, strong positive relationship with contraceptive use. Women who had nonvoluntary intercourse and teenagers with significantly older partners were less likely to use contraceptives. Condoms are appropriate for infrequent intercourse, but couples must know the risks of pregnancy even with infrequent intercourse and know about postcoital methods of pregnancy prevention.

The role of reproductive factors and use of oral contraceptives in the aetiology of breast cancer in women aged 50 to 74 years.

It is unclear whether age at menarche is causally involved in breast-cancer aetiology, or serves a correlate of other early-life exposures. Other aspects of reproductive life, including cycle length and regularity, climacteric symptoms, reproductive history and oral contraceptive use, are also incompletely investigated. We examined these issues in a population-based case-control study, including 3,016 women aged 50 to 74 years with invasive breast cancer, and 3,263 controls of similar age. Mailed questionnaires and telephone interviews were used to collect information on menstrual and reproductive characteristics as well as use of oral contraceptives. We found a statistically significant negative association between increasing age at menarche and breast-cancer risk in women born before 1925 but not after. Length of the menstrual cycle at age 30 seemed to be adversely related to breast-cancer risk, with OR for women with cycle lengths < 24 days and > 30 days being 0.76 and 1.18, as compared with women with a cycle length of 28 days. There was a strong trend of decreasing breast-cancer risk with increasing parity (OR per borne child 0.85, 95% CI 0.80-0.90). Lactation, menopausal symptoms or past use of oral contraceptives did not appear associated with breast-cancer risk. Our findings provide some evidence of a role of environmental correlates of early menarche in breast-cancer aetiology, and underline the importance of childbirth, especially early in life, in the prevention of breast cancer. Our data are not readily compatible with an important influence of former oral contraceptive use on post-menopausal breast-cancer risk.

PIP: An epidemiological study was conducted in Sweden to determine the role of reproductive factors and use of oral contraceptives (OCs) in the etiology of breast cancer in 3016 women aged 50-74 years, with 3263 serving as controls. Mailed questionnaires and telephone interviews requesting detailed information on menstrual history, including ages at menarche and menopause, cycle length, cycle regularity, interruption of cycling and climacteric symptoms, were obtained. Results showed that risk was almost twice as high among women with menarche at age 11 or younger as compared to those with menarche at age 17 or later. The length of the menstrual cycle at age 30 was positively related to breast cancer risk, but there was no convincing association between either irregularity of the menstrual cycle at age 30 or amenorrhea for at least 6 months and breast cancer risk. Fecundity, lactation, menopausal symptoms, and use of combined oral contraceptives were insignificantly related with breast cancer risk. Therefore, the findings of this large population-based study provide evidence of the role of environmental correlates of early menarche in breast cancer etiology, rather than to the hormonal effects of early menarche. Furthermore, this stresses the importance of childbearing, especially early in life, to prevent breast cancer.

Estimates of the risk of cardiovascular death attributable to low-dose oral contraceptives in the United States.

OBJECTIVE: Our purpose was to estimate the annual risk of death in the United States from cardiovascular disease attributable to low-dose combination oral contraceptives. STUDY DESIGN: Estimates of the risk of death from cardiovascular disease attributable to low-dose oral contraceptives were modeled on data from studies published through 1997 and from age-specific mortality rates in the United States for 1993 and 1994. RESULTS: Attributable risk of death from cardiovascular disease resulting from oral contraceptive use is 0.06 and 3.0 per 100,000 nonsmokers 15 to 34 years of age and 35 to 44 years of age, respectively. In smokers this risk increases, respectively, to 1.73 and 19.4 per 100,000 users in these 2 age groups; however, 97% and 85% of this risk is due to the combined effects of smoking and using oral contraceptives. The attributable risk of death from cardiovascular disease in nonsmoking oral contraceptive users is lower than the risk of death from pregnancy in nonusers of oral contraceptives at all ages; however, among smoking oral contraceptive users more than 35 years of age, the excess risk of death from oral contraceptives is higher than the risk of death from pregnancy. CONCLUSION: There is virtually no excess attributable risk of death from cardiovascular disease related to oral contraceptive use in young women. However, smokers more than 35 years of age should use a nonestrogen contraceptive.

PIP: The annual risk of death in the US from cardiovascular disease attributable to low-dose combination oral contraceptives (OCs) was estimated through use of data from studies published in 1980-1997 and from age-specific mortality rates for 1993 and 1994. Four cardiovascular disease categories were included: myocardial infarction, venous thromboembolism and pulmonary embolism, ischemic stroke, and hemorrhagic stroke. The overall risk of death from cardiovascular disease among nonsmoking users of low-dose OCs is 0.06/100,000 women in the 15-34 year age group and 3.03/100,000 women in the 35-44 year age group. For young nonsmokers, the excess mortality risk associated with OC use is smaller than the risk of death from pregnancy, whether terminated by abortion or carried to term. Among OC users who smoke, the risk of cardiovascular mortality is 1.73/100,000 in 15-34 year olds and 19.4/100,000 in women 35-44 years old; however, 97% and 85% of this risk, respectively, is composed of the combined OC-smoking risk. Among smoking OC users over 35 years of age, the excess risk of death from OCs exceeds the risk of death from pregnancy. Young nonsmokers raise their risk of death from cardiovascular disease by less than 10% (0.60-0.65/100,000) by using OCs, while young women who do not use OCs increase their risk of death by 260% (0.60-1.57/100,000) by smoking cigarettes. For older women, the corresponding increases are 95% among nonsmoking OC users and 315% among smoking nonusers. These estimates indicate that women over 35 years of age who smoke should not be permitted to use either low- or high-dose OCs because of the excess attributable risk of death from cardiovascular disease.

Oral contraceptives and the risk of subarachnoid hemorrhage: a meta-analysis.

OBJECTIVE: The objective of this study is to estimate the risk of subarachnoid hemorrhage produced by oral contraceptive use. METHODS: Studies published since 1960 were identified using MEDLINE, Cumulated Index Medicus, Dissertation Abstracts On-line, and bibliographies of pertinent articles. Two independent reviewers screened published cohort and case-control studies that evaluated the risk of subarachnoid hemorrhage associated with oral contraceptives. Eleven of 21 pertinent studies met predefined quality criteria for inclusion in the meta-analysis. Relative risk (RR) estimations evaluating subarachnoid hemorrhage risk in oral contraceptive users compared with nonusers were extracted from each study by two independent reviewers. Study heterogeneity was assessed by design type, outcome measure (mortality versus incidence), exposure measure (current versus ever use), prevailing estrogen dose used, and control for smoking and hypertension. RESULTS: The overall summary RR of subarachnoid hemorrhage due to oral contraceptive use was 1.42 (95% CI, 1.12 to 1.80; p = 0.004). When the two study results failing to control for smoking were excluded from the analysis, a slightly greater effect was seen, with an RR of 1.55 (95% CI, 1.26 to 1.91; p < 0.0001). In the six studies controlling for smoking and hypertension the RR was 1.49 (95% CI, 1.20 to 1.85; p = 0.0003). High-estrogen oral contraceptives appeared to impart a greater risk than low-dose preparations in studies controlling for smoking, but the difference was not significant (high-dose RR, 1.94; 95% CI, 1.06 to 3.56; low-dose RR, 1.51; 95% CI, 1.18 to 1.92). CONCLUSIONS: This meta-analysis of observational studies suggests that oral contraceptive use produces a small increase in the risk of subarachnoid hemorrhage.

PIP: Both case-control and cohort studies have evaluated the risk of subarachnoid hemorrhage (SAH) among oral contraceptive (OC) users and identified relative risks as low as 0.5 and as high as 6.5. To determine whether OC use is indeed a risk factor for SAH after accounting for the variability in study designs and results, a meta-analysis was conducted of the 11 salient independent studies included in the research literature. The summary estimate of effect for all studies was a relative risk (RR) of 1.42 (95% confidence interval (CI), 1.12-1.80). There was a trend toward smaller RRs in the most recent studies, presumably as a result of decreases in the estrogen dose of modern OCs. In the 6 studies that controlled for both smoking and hypertension, the summary RR was 1.49 (95% CI, 1.20-1.85). Only 2 of the 11 studies found a protective effect of current OC use on SAH risk, and it was nonsignificant. Taken together, these studies support a weak positive association between OC use and SAH risk. In the US, an additional 430 patients each year with OC-related SAH would be expected. For most women, the SAH risk is inconsequential in evaluating the decision about OC use. However, for women at high risk of SAH due to unruptured aneurysms, a strong positive family history, smoking, or hypertension, it may be advisable to consider alternative contraceptive methods until more data are available.

Oral contraceptives and breast cancer risk in Taiwan, a country of low incidence of breast cancer and low use of oral contraceptives.

One hundred and seventy four (81% of all) pathologically confirmed new incident cases of female breast cancer identified from a medical center in Taipei from February, 1993 to June, 1994 were selected as the case group. Four hundred and fifty three inpatient controls who were without obstetric-gynecological, breast, or malignant diseases were individually matched for each case by age and date of admission. Information was obtained through direct interview and review of medical records. Conditional logistic regression was used to estimate the effects of each risk factor. After adjusting for education level, body mass index, age at menarche and first full-term pregnancy, parity, menopausal status and age at menopause, lifetime lactation, use of lactation inhibition hormones, and family history of breast cancer, breast cancer risk significantly elevated in use of OC before 25 years old and before 1971. In stratified analysis, significantly higher risk were found in OC use before 25 years old and in duration of use less than one year among post-menopausal subjects. Our results support the notion that OC use in early life for younger women and in early calendar years increase breast cancer risk.

PIP: The effects of oral contraceptive (OC) use on the risk of breast cancer were investigated in a hospital-based case-control study conducted in Taiwan--a country with low use of OCs and a low incidence of breast cancer. 174 consecutive new incident cases of breast cancer diagnosed at National Taiwan University Hospital in Taipei in a 16-month period in 1993-94 and 435 age-matched controls admitted to the same hospital during the study period with nongynecologic, nonmalignant conditions were enrolled. 25 cases (14.4%) and 47 controls (10.4%) had ever used OCs; 9 cases (5.2%) and 15 controls (3.3%) had used the pill for 5 years or more. The risk of breast cancer was moderately elevated in OC users who started pill use before 25 years of age or before 1971, when the hormonal content of OCs was stronger. After adjustment for educational level, body mass index, ages at menarche and first full-term pregnancy, parity, menopausal status and age at menopause, lactation, family history of breast cancer, and use of female sex hormones other than OCs, the adjusted odds ratio (OR) for OC use was 1.7 (95% confidence interval (CI), 0.9-3.2). The adjusted OR for OC use before 25 years of age vs. never use was 3.4 (95% CI, 1.2-9.7). The adjusted OR for OC use before 1971 compared with never use was 3.2 (95% CI, 1.2-8.9). In premenopausal women, the adjusted OR for age at first use under 25 years of age compared with never use was 5.8 (95% CI, 1.5-22.1) and the adjusted OR for duration of OC use of 5 or more years vs. never use was 3.5 (95% CI, 0.9-14.3). For postmenopausal women, the adjusted OR of duration of OC use less than 1 year vs. never use was 7.5 (95% CI, 1.1-50.1).

Oral contraceptives and thrombosis.

PIP: Recent studies have identified an increased risk of venous thromboembolism associated with use of third-generation oral contraceptives (OCs). Use of these newer formulations has been estimated to cause an excess of 10 deaths/year in the UK. The possibility has been raised, however, that prescribing bias and confounding by duration of OC use and other personal risk factors accounts for the difference in the risk of venous thromboembolism between second- and third-generation OCs. Other studies have identified an increased risk of myocardial infarction and stroke in OC users, including users of low-dose formulations, but this risk is almost exclusively limited to older women who smoke or have other cardiovascular risk factors. The interpretation of all such studies on OC side effects should take into account that the absolute risk of an adverse thrombotic event while taking OCs is small. This risk appears to be affected far more by factors such as smoking, age, hypertension, and familial disorders than the type of progestagen contained in the OC.^ieng

Human papillomavirus and human immunodeficiency virus infections: relation with cervical dysplasia-neoplasia in African women.

Our study assessed the factors associated with cervical squamous intra-epithelial lesions (SILs) and invasive cervical cancer, with special attention to human immunodeficiency virus (HIV) and human papillomavirus (HPV) infections. Women from 3 outpatient gynecology clinics of Abidjan, Côte d'Ivoire, were screened for cervical abnormalities: 151 women with low-grade SILs and 151 controls, 60 with high-grade SILs and 240 controls, and 13 with invasive cancer and 65 controls were enrolled in 3 case-control studies. Controls were chosen at random among the women without lesions, with a frequency matching for age and center. We used the PCR method for the detection of cervical HPV DNA and the restriction fragment length polymorphism analysis for HPV typing. HIV antibody testing and CD4 cell count were performed. In multivariate analyses, factors associated with cervical lesions were: for low-grade SILs, HPV positivity, HIV-1 seropositivity and parity >3; for high-grade SILs, HPV positivity, chewing tobacco, HIV-1 seropositivity and illiteracy, and for invasive cancer, HPV positivity only. We found a diversity of HPV types associated with SILs. In HIV-1-infected women, SILs occurred at an early stage of HIV disease. Women infected with both HIV-1 and HPV were at much higher risk of SILs than women infected with each of these 2 viruses separately. Invasive cancer was linked to HIV-2 infection in univariate analysis only. Our results suggest that the relation of SILs with HIV-1 infection is mainly explained by HPV infection and that HIV-1-infected African women may not often reach the invasive stage of cervical cancer.

PIP: The factors associated with cervical squamous intraepithelial lesions (SILs) and invasive cervical cancer were assessed in case-control studies of women from 3 outpatient gynecology clinics in Abidjan, Ivory Coast. Enrolled were 151 women with low-grade SILs and 151 controls, 60 women with high-grade SILs and 240 controls, and 13 women with invasive cervical cancer and 65 controls. Human papillomavirus (HPV) was detected in 75% of the high-grade SILs and cancers compared to 20% in the age-matched control groups. In the multivariate analysis, low-grade SILs were associated with HPV positivity, HIV-1 seropositivity, and parity above 3; for high-grade SIL, these risk factors were HPV positivity, chewing tobacco, HIV-1 seropositivity, and illiteracy. Cervical cancer was associated only with HPV positivity. Women infected with both HPV and HIV-1 were at a significantly higher risk of SILs than women infected with only one of these two viruses. These findings suggest that the association of SILs with HIV-1 infection is primarily explained by HPV infection and that HIV-infected African women may not live to reach the invasive stage of cervical cancer. The feasibility of cervical screening directed preferentially to African women with a low educational level or multipara merits assessment.

The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross-sectional and prospective studies in pre-menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre-menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post-menopausal fracture risk is increased. The present study addresses this question. DESIGN: Cross-sectional study of bone density in post-menopausal former users of DPMA and controls. SUBJECTS: Three hundred and forty-six normal post-menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years. MEASUREMENTS: Bone density was measured in the spine, proximal femur and total body by dual-energy, X-ray absorptiometry. RESULTS: There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non-users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause. CONCLUSIONS: Any residual effects of depot medroxyprogesterone acetate use on post-menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post-menopausal years.

PIP: The possibility that use of depot medroxyprogesterone acetate (DMPA) has residual effects on postmenopausal bone mineral density was assessed in a cross-sectional study of 346 postmenopausal former users of DMPA and controls from Auckland, New Zealand. 34 women (10%) reported past use of DMPA, for a median duration of 3 years, starting at a median age of 41 years. Dual-energy, x-ray absorptiometry failed to reveal significant differences between past users of DMPA and never-users in bone density in the spine, proximal femur, or total body. However, in women who had used DMPA for more than 2 years, there was a nonsignificant trend toward lower bone densities in former users compared with never-users. The difference between mean measurements was 1.6% in the lumbar spine (p = 0.6), 3.1% in the femoral neck (p = 0.4), and 0.5% in the total body (p = 0.8). There was no correlation between bone densities and the duration of DMPA use, age at discontinuation of DMPA use, or the time between DMPA discontinuation and menopause. These findings suggest that any residual effects of DMPA use on postmenopausal bone density are likely to be small and without a substantial impact on fracture risk.

Bone density among long-term users of medroxyprogesterone acetate as a contraceptive.

The bone density (BD) of 72 women using depot-medroxyprogesterone acetate (DMPA) for at least 1 year was compared with that of 64 women who were not users of hormonal contraceptives. The BD of lumbar spine, femoral neck, Ward's triangle, and trochanter was measured by dual energy X-ray absorptiometry (DEXA-LUNAR DPX). Estradiol (E2) concentrations were measured by radioimmunoassay (RIA). The mean age of DMPA users and nonusers was 31.8 and 31.1 years, respectively. Mean E, was 55.7 pg/mL for users and 149.9 pg/mL for controls (p < 0.001). The BD was significantly lower for DMPA users than for controls in all sites (p < 0.01). In addition, young adult T-scores in the lumbar spine were significantly lower among DMPA users than in controls (p < 0.01). Differences were maintained in a subsample of 47 women per group paired by age and body mass index (BMI). Multiple regression analysis showed that older age, lower BMI, and longer amenorrhea were associated with lower BD in the femoral neck, whereas lower BMI and use of DMPA were associated with lower BD in the lumbar spine.

PIP: Family planning programs that offer depot medroxyprogesterone acetate (DMPA) cannot be indifferent to the risk of lowered bone density. A study conducted at the Family Planning Clinic of the State University of Campinas (Sao Paulo, Brazil) compared bone densities in 72 women who had been using DMPA for at least 1 year (mean duration, 42 months) and 64 regularly menstruating nonusers. Mean age was 31 years in both groups; there were no significant differences between the 2 groups in terms of ethnicity, body mass index (BMI), or smoking. Mean serum estradiol concentrations were 55.7 +or- 40.5 pg/ml for DMPA users and 149.9 +or- 88.2 pg/ml for nonusers (p 0.001). The mean length of amenorrhea was 26.5 +or- 23.8 months among DMPA users. The mean bone density in DMPA users was significantly lower than that of controls at all sites evaluated (i.e., lumbar spine, femoral neck, Ward's triangle, and trochanter). 38 DMPA users, compared with only 17 controls, had a T-score in the lumbar spine lower than -1 standard deviation (p = 0.014). Multiple regression analysis identified BMI and DMPA use as variables significantly associated with bone density in the lumbar spine; in the femoral neck, these variables were BMI, age, and length of amenorrhea. Periodic bone densitometry should be considered for women over 40 years of age with low BMI who have more than 2 years of continuous amenorrhea.

Can intrauterine device removals for bleeding or pain be predicted at a one-month follow-up visit? A multivariate analysis.

From 4%-14% of intrauterine device (IUD) users have their IUD removed due to bleeding or pelvic pain in the first year of use. Past studies have analyzed whether baseline patient information can help predict such removals, but no previous analysis has examined whether information provided at the recommended 1-month follow-up visit could improve such predictions. Using data from an international multicenter randomized controlled trial, 89 women with removals for bleeding and pain after the 1-month visit were compared with 2536 continuing users. Logistic regression indicated several significant predictors of removal. Women reporting intermenstrual bleeding since last menses were nearly three times more likely to have removals for bleeding or pain (odds ratio [OR] 2.9; 95% confidence interval [CI] 1.4-5.9). Similarly, those complaining of excessive menstrual flow were 3.5 times more likely to have removals within 12 months (95% CI 1.4-9.2). Women reporting these menstrual problems during scheduled revisits may benefit from counseling and treatment with nonsteroidal anti-inflammatory drugs (NSAID).

PIP: In the first year of use, 4-14% of IUD users have the device removed because of pelvic pain or bleeding. Identification of women at risk of removal for these reasons would enable targeted counseling and treatment, thereby reducing the frequency of removal requests. The hypothesis that problems reported at the 1-month follow-up visit can help to predict eventual IUD removal for pain or bleeding was investigated through use of data from a randomized controlled trial of IUD acceptors from 18 centers in 14 countries in Asia, Africa, and Latin America, who were followed for 1 year. The present analysis was restricted to 2536 women who received Copper T-380A or Multiload 250 IUDs. There were 89 removals for pain or bleeding during the study period. When baseline acceptor characteristics were considered, breast-feeding status was the most significant predictor of removal. Women not breast feeding at the time of IUD insertion were 2.8 times (95% confidence interval (CI), 1.5-5.2) as likely as those who were breast feeding to undergo removal for pain or bleeding in the 12 months after insertion. The following variables reported at the 1-month follow-up visit were significant predictors of removal: intermenstrual bleeding since last menses (odds ratio [OR], 1.9; 95% CI, 1.4-5.9), excessive menstrual flow (OR, 3.5; 95% CI, 1.4-9.2), and cessation of breast feeding since IUD insertion (OR, 2.2; 95% CI, 0.9-5.6). Although intermenstrual pelvic pain, spotting, and menstrual flow of more than 1 week's duration increased the risk of removal, they were not statistically significant predictors in this sample. Women who report intermenstrual bleeding or excessive menstrual flow at their 1-month follow-up visit may benefit from counseling and, in some cases, treatment with nonsteroidal anti-inflammatory drugs to reduce their risk of early IUD discontinuation.

Ovarian pregnancy; relationship to an intrauterine device.

Ovarian pregnancy is a rare form of ectopic pregnancy in which the gestational sac is implanted within the ovary. The incidence is 0.5 to 3% of all ectopic gestations. In contrast to patients with tubal pregnancies, traditional risk factors, such as pelvic inflammatory disease and prior surgical procedure upon the pelvis, may not play a role in the aetiology. In the 2 cases reported here, it seems that using an intrauterine contraceptive device was an important factor.

PIP: The etiology of primary ovarian pregnancy is unknown, although an IUD is frequently implicated. This paper presents two cases of primary ovarian pregnancy diagnosed at Dokuz Eylul University in Izmir, Turkey, in 1995 and discusses the pathogenesis in relation to the IUD. In the first case, the woman had used a copper-releasing IUD for 3 years and had had it removed 1 month before presentation. The second woman had been using a Lippes Loop device for 16 years. Ovarian pregnancy was diagnosed only after pathologic examination of the specimen. Both pregnancies were located within the corpus luteum, suggesting that fertilization and nidation occurred at the ovulation site. Although the IUD protects against ectopic pregnancy in the first 24 months of use, the risk increases over time as the reversible foreign-body histologic changes associated with IUD use become established in the Fallopian tube. The preoperative diagnosis of primary ovarian pregnancy is very difficult. It should be kept in mind, however, that ovarian pregnancy is more frequent in ectopic pregnancies associated with IUD use.

Factors affecting perinatal mortality (PNM) in women attending Bab El-Shaaria University Hospital.

PIP: This study aimed to identify and to assess the important factors affecting perinatal mortality (PNM) in Cairo. 200 women were selected randomly from the gynecology and obstetric department of Bab El-Shaaria University Hospital. 100 women were the case group of perinatal deaths, while the other 100 women formed the control group. Both groups had similar life styles. The attendance rate for prenatal care was more frequent among the control group. High parity, short birth intervals, twins, preterm births, a birth order of 4 or higher, anemia, diabetes mellitus, and maternal age of 30 years and older were more prevalent among the case group and considered risk factors for perinatal mortality. Adequate health care and family planning services must be available to all women of reproductive age. Good prenatal care is needed for the prevention and control of coexisting diseases, and good obstetric care is needed to prevent the premature rupture of membranes.^ieng

Incident HIV-1 infection in a cohort of young women in Butare, Rwanda.

OBJECTIVE: To determine the incidence of HIV-1 infection and associated risk factors among young, seronegative, and sexually active women in a mixed rural and urban population in southern Rwanda. DESIGN: A prospective cohort study. METHODS: Between October 1991 and April 1993, we completed a 2-year follow-up survey among HIV-1-seronegative women aged < or = 30 years at the time of their initial HIV-1 screening during pregnancy. All women aged < or = 25 years and a randomly selected sample of 26-30-year olds were invited to participate from five prenatal clinics in the Butare region. The interview focused on potential risk factors for HIV-1 acquisition during the 2-year interval between blood collection. RESULTS: Out of 1524 women selected, 1150 (75%) participated in the follow-up survey. The 2-year incidence of HIV-1 infection was 2.7% [95% confidence interval (CI), 1.8-3.9]. Teenage women were at the highest risk (incidence, 10.5%; 95% CI, 5.2-19.4), with incidence leveling off with increasing age (P < 0.001). Women who began sexual activity recently were also at higher risk; the lowest risk category consisted of women aged 26-30 years with 5 or more years of sexual experience. The more urban the geographic residence of the woman, the more likely she was to have acquired HIV-1 infection (P < 0.001). In the urban and peri-urban zones, the poorest women were at significantly higher risk of incident HIV-1 infection than women reporting higher household income. In a multivariate analysis, young maternal age, marital status (being single, divorced or widowed), multiple sexual partners, and a history of sexually transmitted diseases remained strongly associated with incident HIV-1 infection. Geographic residence, hormonal contraception, and receipt of injections were no longer significantly associated with incident HIV-1 infection when these other factors were accounted for simultaneously. CONCLUSION: Among young Rwandan women, the early years of sexual activity are particularly dangerous for acquisition of HIV-1 infection. Interventions should focus on young teenagers before they become sexually active.