Article

Impact of Estrogen Type on Cardiovascular Safety of Combined Oral Contraceptives

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Abstract

Objectives: The International Active Surveillance study "Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) investigated the cardiovascular risks associated with the use of a combined oral contraceptive (COC) containing dienogest and estradiol valerate (DNG/EV) compared to established COCs in a routine clinical setting. Study design: Transatlantic, prospective, noninterventional cohort study conducted in the United States and seven European countries with two main exposure groups and one exposure subgroup: new users of DNG/EV and other COC (oCOC), particularly levonorgestrel-containing COCs (LNG). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious cardiovascular events (SCE), particularly venous thromboembolic (VTEs) events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Results: A total of 50,203 new COC users were followed up for up to 5.5years (mean value, 2.1years). Overall 20.3% and 79.7% of these women used DNG/EV and oCOC (including 11.5% LNG users), respectively. A low loss to follow-up of 3.1% was achieved. Based on 47 (VTE) and 233 (SCE) events, the primary analysis (European data set) yielded adjusted hazard ratios for DNG/EV vs. oCOC of 0.4 and 0.5, respectively. The upper bounds of the 95% confidence intervals were 0.98 (VTE) and 0.96 (SCE). The corresponding hazard ratios for DNG/EV vs. LNG showed similar point estimates but the confidence intervals included unity. Conclusion: DNG/EV is associated with similar or even lower cardiovascular risk compared to oCOC and LNG. Implication statement: A COC containing DNG and EV is associated with similar or even lower cardiovascular risk compared to COCs containing levonorgestrel or other progestogens.

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... The 2016 results of the first epidemiological studies of these E 2 -based formulations were highly encouraging [5,6] (updated results were published in 2020 [7]). The International Active Surveillance Study -Safety of Contraceptives: Role of Oestrogens (INAS-SCORE) [5,7] investigated the cardiovascular risks associated with the use of the combined hormonal contraceptive E 2 V/DNG. ...
... The 2016 results of the first epidemiological studies of these E 2 -based formulations were highly encouraging [5,6] (updated results were published in 2020 [7]). The International Active Surveillance Study -Safety of Contraceptives: Role of Oestrogens (INAS-SCORE) [5,7] investigated the cardiovascular risks associated with the use of the combined hormonal contraceptive E 2 V/DNG. The final report described the results of 10,191 E 2 V/DNG users compared with those of 41,012 women using other EEbased COCs (5796 of whom were using EE/LNG-based products). ...
... The very low incidence rate in the PRO-E2 study is very similar to that traditionally reported in combined hormonal contraceptive non-use cohorts (2-3 cases/10,000 users per year) [4,7]. The methods for VTE case evaluation in the two trials were, however, similar: after the first report of an adverse event such as a VTE, three independent adjudicators (specialised in radiology/nuclear medicine, cardiology and internal medicine/phlebology), blinded to the type of hormonal treatment used and unaware of how the investigators had previously classified events, recorded VTEs as 'confirmed' or 'not confirmed' [5,7,8]. Only in the PRO-E2 study, however, was a number of 'potential' VTE cases reported, when a specific case could be not adjudicated because of insufficient information (e.g., medical documentation) ( Reed et al. [8] discuss other potential reasons for the lower incidence found in their study (e.g., very low occurrence in the Russian dataset), but these may not completely explain the full picture. ...
... Although EE has been used in numerous COCs, efforts have also been made to use estradiol and estradiol valerate (EV), which have a lower impact on the hepatic system and subsequently on hemostatic parameters [2]. In 2016 we published initial cardiovascular safety data from the "International Active Surveillance Study on the Safety of Contraceptives and the Role of Estrogens" (INAS-SCORE) which compared the safety profile of a new EV-based COC with established COCs containing EE [3]. We concluded that the EV-containing COC is associated with similar or even lower cardiovascular risk compared to EE-containing COCs -including combinations of levonorgestrel (LNG) and EE. ...
... We conducted a prospective, non-interventional cohort study of more than 50,000 new COC users to assess the occurrence of rare or unexpected adverse outcomes possibly related to COC exposure. The methodology and initial results of the INAS-SCORE study have been reported previously [3]. Here we present the results of the extension of the follow-up phase of the study. ...
... Mean age in the DNG/ EV exposure group was 5.7 years higher than that in the COC and LNG/EE (sub)-groups; the 75th age percentile of DNG/EV exceeds the oCOC figure by about 10 years. The reasons for the age differences between the cohorts were discussed in our previous report [3]. ...
... INAS-SCORE, a large, transatlantic, prospective, controlled, non-interventional, long-term cohort study, investigated the occurrence of cardiovascular events between two cohorts: women initiating use of E2V/DNG and women initiating other COCs, including LNG-containing COCs [11]. These real-world data showed that the use of E2V/DNG was associated with a similar or even lower risk of confirmed VTE compared with LNG-containing COCs and other COCs [11]. ...
... INAS-SCORE, a large, transatlantic, prospective, controlled, non-interventional, long-term cohort study, investigated the occurrence of cardiovascular events between two cohorts: women initiating use of E2V/DNG and women initiating other COCs, including LNG-containing COCs [11]. These real-world data showed that the use of E2V/DNG was associated with a similar or even lower risk of confirmed VTE compared with LNG-containing COCs and other COCs [11]. ...
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Purpose: To evaluate differences in key outcomes between younger and older women receiving the oral contraceptive oestradiol valerate/dienogest (E2V/DNG). Methods: We conducted a pooled post hoc analysis of primary data from 12 studies of E2V/DNG, stratified by age (≤25 [n = 1309] and >25 [n = 2132] years). Outcomes included safety, efficacy, bleeding profile and hormone-withdrawal-associated symptoms (HWAS). Bleeding and HWAS analyses are also presented for women aged ≤20 years (n = 362). Discontinuations were considered a proxy for patient satisfaction. Results: Results were generally similar for younger and older women. The percentage of women aged ≤25 and >25 years experiencing intracyclic bleeding did not differ between groups (13.4% and 12.8% at cycle 12, respectively), with similar results in women aged ≤20 years (12.7%, cycle 12). Rates of withdrawal bleeding were very similar in women aged ≤25 and >25 years (78.5% and 78.9%, respectively, cycle 12). We also found a similar adjusted Pearl index in the two age groups (0.45 vs 0.57, respectively), similar rates of AEs and HWAS and no difference in discontinuations. Conclusions: Women aged ≤25 and >25 years have a similar experience with an E2V/DNV oral contraceptive, supporting this as an appropriate contraceptive option in younger and older women.
... Twenty micrograms of EE are approximately equivalent to 2 mg of 17βE valerate, the latter appearing to have a milder impact on hemostasis, fibrinolysis markers and lipid profile compared to EE [39,44]. However, whether 17βE-containing COC are safer than those formulated with EE in terms of thromboembolism still needs to be systematically demonstrated [45,46]. ...
... In patients with Turner syndrome, several studies demonstrated a suboptimal uterine development in patients treated with EE for pubertal induction [68,69]. Conversely, transdermal 17βE has shown better results in terms of uterine parameters [45,46] On the other hand, conflicting outcomes have been reported about the effectiveness of oral 17βE in achieving a complete development of uterine volume, with some supporting the hypothesis of a good response and others advising against its use in this specific setting [70][71][72]. ...
Article
In women with premature ovarian insufficiency (POI), hormonal therapy (HT) is indicated to decrease the risk of morbidity and to treat symptoms related to prolonged hypoestrogenism. While general recommendations for the management of HT in adults with POI have been published, no systematic suggestions focused on girls, adolescents and young women with POI following gonadotoxic treatments (chemotherapy, radiotherapy, stem cell transplantation) administered for pediatric cancer are available. In order to highlight the challenging issues specifically involving this cohort of patients and to provide clinicians with the proposal of practical therapeutic protocol, we revised the available literature in the light of the shared experience of a multidisciplinary team of pediatric oncologists, gynecologists and endocrinologists. We hereby present the proposals of a practical scheme to induce puberty in prepubertal girls and a decisional algorithm that should guide the clinician in approaching HT in post-pubertal adolescents and young women with iatrogenic POI.
... Another meta-analysis also indicated a considerably increased risk of VTE for desogestrel, drospirenone, gestodene, and CPA compared to levonorgestrel, when combined with EE (30 to 40 μg) ( Table 2). No increased risk of VTE was reported for gestodene/EE 20 μg [48] and dienogest/ E2V [49] combinations. ...
Article
Polycystic ovary syndrome (PCOS) is a common endocrine disorder in reproductive-aged women, characterized by hyperandrogenism, oligo/anovulation, and polycystic ovarian morphology. Combined oral contraceptives (COCs), along with lifestyle modifications, represent the first-line medical treatment for the long-term management of PCOS. Containing low doses of estrogen and different types of progestin, COCs restore menstrual cyclicity, improve hyperandrogenism, and provide additional benefits such as reducing the risk of endometrial cancer. However, potential cardiometabolic risk associated with these agents has been a concern. COCs increase the risk of venous thromboembolism (VTE), related both to the dose of estrogen and the type of progestin involved. Arterial thrombotic events related to COC use occur much less frequently, and usually not a concern for young patients. All patients diagnosed with PCOS should be carefully evaluated for cardiometabolic risk factors at baseline, before initiating a COC. Age, smoking, obesity, glucose intolerance or diabetes, hypertension, dyslipidemia, thrombophilia, and family history of VTE should be recorded. Patients should be re-assessed at consecutive visits, more closely if any baseline cardiometabolic risk factor is present. Individual risk assessment is the key in order to avoid unfavorable outcomes related to COC use in women with PCOS.
... CHC use is associated with a 3-fold increase risk for VTE with an absolute risk of 3-4 per 10,000 in adolescents. There currently is inadequate data to support preferential prescribing related to increased VTE risk based on type of progestin or dose of ethinyl estradiol (82). Prospective cohort studies do not seem to show a significant difference in VTE risk by progestin type (83,84). ...
Article
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Although pregnancy and abortion rates have declined in adolescents, unintended pregnancies remain unacceptably high in this age group. The use of highly effective methods of contraception is one of the pillars of unintended pregnancy prevention and requires a shared decision making process within a rights based framework. Adolescents are eligible to use any method of contraception and long-acting reversible contraceptives, which are “forgettable” and highly effective, may be particularly suited for many adolescents. Contraceptive methods may have additional non-contraceptive benefits that address other needs or concerns of the adolescent. Dual method use should be encouraged among adolescents for the prevention of both unintended pregnancies and sexually transmitted infections. Health care providers have an important role to play in ensuring that adolescents have access to high quality and non-judgmental reproductive health care services and contraceptive methods in adolescent-friendly settings that recognize the unique biopsychosocial needs of the adolescent.
... Compared to EE, the effect of the natural human hormone estradiol (E2) on hepatic metabolism is reduced [2,3]. Therefore, replacing EE with E2 in a COC is associated with fewer metabolic effects, an improved safety profile [4,5] and a similar or even lower cardiovascular risk compared to other COCs [6]. The type of progestin used in COCs also determines their endocrine and metabolic effects. ...
Article
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Objectives To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). Study Design Randomized, open-label, controlled, three-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) (n=38), or ethinylestradiol (EE) 30 µg/ levonorgestrel (LNG) 150 µg (n=29), or EE 20 µg/ DRSP 3 mg (n=31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. Results At Cycle 6, E4/DRSP treatment had less effect on gonadotropins (FSH +30.5%, LH -7.5%) compared to EE/LNG (FSH -84.0%, LH -92.0%) and EE/DRSP (FSH -64.0%, LH -90.0%). With E4/DRSP increases in total cortisol (+26.0%) and CBG (+40%) were less compared to EE/LNG (cortisol +109%, CBG +152.0%) and EE/DRSP (cortisol +107%, CBG +140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen (+75.0%) compared to EE/LNG (+170.0%) and EE/DRSP (+206.5%) and for SHBG (+55.0%), compared to EE/LNG (+74.0%) and EE/DRSP (+251.0%). E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides (+24.0%), which was less compared to EE/LNG (+28.0%) and EE/DRSP (+65.5%). E4/DRSP had no effect on carbohydrate metabolism. Conclusions E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. Implications statement Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.
... To improve the safety profile of EE-containing COCs, the EE dose has been reduced [1]. Another approach has been to replace EE with the naturally occurring 17-estradiol (E2) to decrease the metabolic impact and subsequent thromboembolic risk from the estrogen component [2][3][4]. ...
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Objective To evaluate the effects of estetrol 15 mg/drospirenone 3 mg on ovarian function. Study Design Single-center, randomized, open-label, parallel study in healthy young women with proven ovulatory cycles. Participants received either estetrol 15 mg/drospirenone 3 mg (E4/DRSP) (n=41) or ethinylestradiol 20 µg/drospirenone 3 mg (EE/DRSP) (n=41) in a 24/4-day regimen for 3 consecutive cycles. Follicular size and endometrial thickness were measured by transvaginal ultrasound every three days in cycles 1 and 3. Blood was sampled for hormone analysis. Ovarian function expressed as Hoogland score was based on follicular size, serum estradiol (E2) and progesterone (P) concentrations. Ovulation was defined as a ruptured follicle-like structure >13 mm with serum E2 concentrations >100 pmol/L and serum P concentrations >5 nmol/L. We assessed return of ovulation after treatment cessation, and safety throughout the study. Results None of the participants ovulated with E4/DRSP use, while one participant ovulated once and one participant ovulated twice during EE/DRSP treatment. Most participants had a Hoogland score of 1 (no ovarian activity) in cycle 1 (85.0% and 82.9% of participants on E4/DRSP and EE/DRSP, respectively) and in cycle 3 (65.8% and 83.8%, respectively). E4/DRSP suppressed follicle-stimulating hormone and luteinizing hormone to a lesser extent than E4/DRSP, whereas both treatments comparably suppressed E2 and P and endometrial thickness. Return of ovulation occurred, on average, 15.5 days after E4/DRSP treatment discontinuation. E4/DRSP was safe and well-tolerated. Conclusions E4 15 mg/ DRSP 3 mg results in adequate ovulation inhibition and ovarian function suppression, comparable to a marketed combined oral contraceptive containing EE/DRSP. Implications statement Treatment with E4 15 mg/DRSP 3 mg showed complete ovulation inhibition, despite less suppression of follicle-stimulating hormone and luteinizing hormone compared to EE/DRSP. If it becomes commercially available, E4/DRSP, containing a naturally occurring estrogen, should be as effective as EE/DRSP.
... [11][12][13] Nevertheless, evidence concerning the risk of VTE associated with COC-containing natural estradiol is limited to one study reporting a risk similar to or lower than that associated with other COCs. 14 In contrast with CHC, the risk of VTE is not increased during the use of progestin-only contraceptives. 15 Thus, the various progestin-only contraceptive methods can also be used in women at increased risk of VTE. ...
Article
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Introduction: The increased risk of venous thromboembolism associated with the use of hormonal contraception is well recognized, but evidence regarding hormonal contraception containing natural estradiol is limited. This study aimed to assess the associations between the patterns of use of different systemic hormonal contraceptives and the risk of venous thromboembolism during 2017-2019. Material and methods: All fertile-aged women (15-49 years) living in Finland in 2017 and using hormonal contraception in 2017 and their 1:1 age- and residence-matched controls not using hormonal contraception in 2017 (altogether 587 559 women) were selected from the Prescription Centre. All incident venous thromboembolism cases during 2018-2019 and their 4:1 age-matched controls were further analyzed in a prospective nested case-control design to assess the associations between the use (starting, stopping, continuous vs no use) of different hormonal contraception types and venous thromboembolism. Results: Altogether, 1334 venous thromboembolism cases occurred during the follow-up period (incidence rate 1.14 per 1000 person-years, 95% confidence interval [CI] 1.08-1.20), with an incidence rate ratio of hormonal contraception vs no hormonal contraception use of 1.42 (95% CI 1.27-1.58). Compared with non-use, starting the use of gestodene and ethinylestradiol (adjusted odds ratio [aOR] 2.85; 95% CI 1.62-5.03), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 0.98-2.44), desogestrel and ethinylestradiol (aOR 1.97; 95% CI 0.99-3.92), and transdermal patch releasing norelgestromin and ethinylestradiol (aOR 5.10; 95% CI 1.12-23.16), as well as continuing the use of gestodene and ethinylestradiol (aOR 2.60; 95% CI 1.61-4.21), drospirenone and ethinylestradiol (aOR 1.55; 95% CI 1.02-2.37), cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.66; 95% CI 1.06-2.61), and vaginal ring releasing etonogestrel and ethinylestradiol (aOR 3.27; 95% CI 1.95-5.48) were associated with venous thromboembolism risk. Regarding the type of estrogen, the highest risk was associated with current use (vs non use in the previous 180 days) of ethinylestradiol-containing preparations (aOR 2.20; 95% CI 1.82-2.65), followed by estradiol-containing preparations (aOR 1.39; 95% CI 1.04-1.87) with no risk for progestin-only hormonal contraception. Current use of estradiol-containing preparations was not associated with venous thromboembolism risk after exclusion of cyproterone-acetate and estrogen/ethinylestradiol (aOR 1.05; 95% CI 0.66-1.66). Conclusions: An increased risk of venous thromboembolism is associated with ethinylestradiol-containing combined preparations. The use of estradiol-containing combined preparations confers only a slightly increased risk, possibly driven by cyproterone-containing combined oral contraceptives, whereas the use of progestin-only contraception is not associated with venous thromboembolism.
... The European Medicines Agency requested a meta-analysis of these four prospective cohort studies to clarify whether DNG/ EE carries a different VTE risk compared to LNG/EE. Therefore, the data on DNG/EE and LNG/EE from the following four prospective cohort studies were combined: i) "Long-term Active Surveillance Study for Oral Contraceptives" (LASS) [5]; ii) "International Active Surveillance Study of Women Taking Oral Contraceptives" (INAS-OC) [6]; iii) "Transatlantic Active Surveillance on Cardiovascular Safety of Nuvaring" (TASC) [7]; and iv) "International Active Surveillance Study -Safety of Contraceptives: Role of Estrogens" (INAS-SCORE) [8]. ...
... Для женщин любого возраста немаловажно, что комбинация Э2В/ДНГ оказывала минимальное влияние на метаболические и гемостатические показатели. Это нашло отражение в результатах крупного проспективного контролируемого долговременного когортного исследования INAS-SCORE (International Active Surveillance study "Safety of Contraceptives: Role of Estrogens"), в котором оценивалась частота сердечно-сосудистых событий в двух когортах женщин: принимавших Э2В/ДНГ или другие КОК (включая ЭЭ/ЛНГ) в условиях реальной клинической практики, при этом использование препарата Э2В/ДНГ было связано со сходным или даже более низким риском венозной тромбоэмболии по сравнению с женщинами, получавшими комбинацию ЭЭ/ЛНГ или другие КОК [47]. ...
Article
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By definition, contraception is the prevention of pregnancy and infection from diseases by mechanical, chemical and other contraceptives and methods. According to World Health Organization (WHO) statistics, up to 40% of women of reproductive age still believe that their needs for family planning services are not met during counseling. When recommending contraception, it is important to consider: the characteristics of the potential consumer, the underlying risk of the disease, possible undesirable drug reactions of various drugs, the cost, availability and preferences of the woman herself. Women are often forced to abandon the use of a contraceptive method in connection with adverse events, for example, when using combined oral contraceptives (COCs), they may feel worse (headaches, mood lability, weight gain, swelling, decreased libido) in a hormone-free interval, especially with the reception mode 21/7. Lack of contraception can lead to an increased risk of an unwanted pregnancy. According to statistics in the Russian Federation in 2018, the absolute number of abortions amounted to 567 183, which, according to the UN classification, corresponds to the average level (level of abortion rate per 1000 women of childbearing age). According to clinical practice, there is a relationship between deterioration of well-being and the duration of the hormone-free interval. At the moment, in our country there is the only COC, which has a hormone-free interval of 2 days, containing bioidentical estrogen estradiol valerate and dienogest. According to the Cochrane Library, COCs with a short hormone-free interval are most effective in relation to the clinical manifestations of the estrogen withdrawal syndrome. WHO calls on clinicians to raise womens awareness of modern methods of contraception.
... Compared to EE, oestradiol (E2), oestradiol-valerate (E2V), or estetrol (E4) exhibit lower effects on hepatic metabolism. Therefore, replacing EE with those variants in a COC is associated with fewer metabolic effects [13][14][15][16][17], an improved safety profile, and a lower cardiovascular risk compared to other COCs [18][19][20]. ...
Article
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Purpose: Steroid hormones in hormonal contraceptives influence a variety of metabolic parameters. Mainly, ethinyloestradiol (EE) in combined hormonal contraceptives (CHC) is a potent inducer of hepatic coagulation factors, has an impact on cholesterol and triglyceride levels and glucose tolerance. Progestins in CHC modify the oestrogen effects in different ways, depending on their pharmacologic properties. The metabolic impact of progestin-only contraceptives is generally considered low. Methods: The influence of novel drospirenone (DRSP)-only pill (4 mg DRSP in 24/4 intake) on a variety of lipid-, carbohydrate- and bone metabolic parameters and on haemostatic variables including clotting factors and D-Dimer level was evaluated in comparison to 0.075 mg desogestrel (DSG) during a multicentric, prospective, double-blind, double-dummy clinical trial with 1190 participants over nine treatment cycles. Results: For both DRSP and DSG, there was a decrease in cholesterol (total, HDL, and LDL) and triglyceride levels. No relevant influence on glucose, insulin, and c-peptide levels or bone remodelling markers were detected in both treatment groups. Considering the coagulatory parameters, there was no impact on hemostasis. Conclusions: The results confirm the beneficial properties of the drospirenone-only pill. EudraCT Number: 2011-002396-42
... Finally, formal address inquiries were conducted, where possible (level four activities), to enable interviewers to visit women's homes or send registered letters with confirmation of receipt. The ethics information for the VIPOS study has been published previously 55 . The study was approved by one independent ethics committee/institutional review board at each country, where required. ...
Article
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Endometriosis is a chronic disease that requires a suitable, lifelong treatment. To our knowledge, the Visanne Post-approval Observational Study (VIPOS) is to date the largest real-world, non-interventional study investigating hormonal management of endometriosis. We describe women’s experiences of endometriosis in the real world by considering their symptoms and the diagnostic process in their healthcare setting. Overall, 27,840 women were enrolled from six European countries via networks of gynecologists or specialized centers. Of these, 87.8% of women were diagnosed based on clinical symptoms; the greatest and lowest proportions of women were in Russia (94.1%) and Germany (61.9%), respectively. Most women (82.8%) experienced at least one of the triad of endometriosis-associated pain symptoms: pelvic pain, pain after/during sexual intercourse, and painful menstrual periods. The most frequently reported endometriosis-associated symptoms were painful periods (61.8%), heavy/irregular bleeding (50.8%), and pelvic pain (37.2%). Women reported that endometriosis impacted their mood; 55.6% reported feeling “down”, depressed, or hopeless, and 53.2% reported feeling like a failure or having let down family/friends. VIPOS broadens our understanding of endometriosis based on real-world data by exploring the heterogeneity of symptoms women with endometriosis experience and the differences in diagnostic approaches between European countries. Trial registration: ClinicalTrials.gov, NCT01266421; registered 24 December 2010. Registered in the European Union electronic Register of Post-Authorisation Studies as number 1613.
... The higher failure rates observed in 'real-life' users are largely attributed to non-compliant use (deviating from instructions on the package inserts, e.g., missed pills [3]) [4] and show marked geographical variation [5]. The European Active Surveillance Study on Oral Contraceptives (EURAS-OC) showed a low 'real-use' contraceptive failure rate of 0.75% during the first year of use [6][7][8], while data from the United States (U.S.) arm of the International Active Surveillance of Women Taking Oral Contraceptives (INAS-OC) showed that the lowest pregnancy rate at one year was 2.1%. In the latter study, of all reported unintended pregnancies, 86% were attributed to non-compliance [9]. ...
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Objective To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COCLNG) users in clinical practice. Study design In this observational study, new users¹ of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HRcrude) and adjusted hazard ratios (HRadj). Results Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COCLNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11–0.19) and 200 in COCLNG users (0.41 per 100 WY; 95% CI, 0.35–0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COCLNG user cohort. The HRadj of NOMAC-E2 vs COCLNG was 0.45 (95% CI, 0.34–0.60; adjusted for age, body mass index, gravidity, COC user status, education level). Conclusions NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COCLNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC.
... Regardless of the availability of rich literature regarding safety climate, several prior researchers have reported its unpredictable impact on the safety behavior, particularly in the case of Thailand 's healthcare industry. Besides, in view of Dinger, Do Minh, & Heinemann (2016), the variation is safety behavior has not been adequately explained by effective safety climate. Therefore, it is essential to perform further research for determining the workplace safety practices' impact on the industry's safety behavior (Fang et al.,2015). ...
... The shorter HFI is certainly protective against the estrogen withdrawal that triggers migraine, but the molecular characteristic of natural estrogens along with the type of progestogens could also play a role in limiting the metabolic impact [196,197]. Indeed, a favorable cardiovascular and metabolic profile of E2V, combined with DNG [198], and E2 with nomegestrol acetate (NOMAC) [199] has been shown, thus making natural estrogens ideal candidates to alleviate MM. Even the brand-new COC-containing E4/DRSP administered in a 24/4 regimen has had encouraging results on the hemostatic parameters [200]. ...
Article
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Migraine is a major neurological disorder affecting one in nine adults worldwide with a significant impact on health care and socioeconomic systems. Migraine is more prevalent in women than in men, with 17% of all women meeting the diagnostic criteria for migraine. In women, the frequency of migraine attacks shows variations over the menstrual cycle and pregnancy, and the use of combined hormonal contraception (CHC) or hormone replacement therapy (HRT) can unveil or modify migraine disease. In the general population, 18–25% of female migraineurs display a menstrual association of their headache. Here we present an overview on the evidence supporting the role of reproductive hormones, in particular estrogens, in the pathophysiology of migraine. We also analyze the efficacy and safety of prescribing exogenous estrogens as a potential treatment for menstrual-related migraine. Finally, we point to controversial issues and future research areas in the field of reproductive hormones and migraine.
... Comparativement aux utilisatrices de COC contenant du lévonorgestrel, l'incidence de TEV était légèrement inférieure chez les utilisatrices d'E2V/diénogest et d'E2/ acétate de nomégestrol (Tableau 2). Cela suggère que l'E2V/lévonorgestrel n'est pas la seule option pour minimiser le risque de TEV associé à l'utilisation de COC, mais que les produits contenant de l'E2(V) sont au moins tout aussi sûrs (49). Cela montre également que ces investigations biologiques peuvent, au moins en partie, être corrélées avec les données épidémiologiques. ...
... All of these are beneficial but are similar in terms of VTE risk and are between 50 and 80% more likely than Levonogestrel. 40,42,45 This fact is evidenced by the studies presented in Chart 1. [46][47][48][49][50] Chart 1 describes five cohorts 46-50 that evaluated the types of estrogen and progestogenas well their combinationand the relative risk of thrombotic events within distinct multivariate analyses. The analysis of the studies mentioned in Chart 1 may have limitations due to do not consider the dosage, do not control all factors of confusion and different study methodologies. ...
Article
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Women have metabolic, immunological, and genetic variables that ensure more protection from coronavirus infection. However, the indication of treatment for several pathologies and contraception is determined by hormones that have adverse effects and raise doubts about their use during the COVID-19 pandemic. Therefore, the present study searches women specificities and the relation between female sexual hormones and COVID-19, and reports the main recommendations in this background. To this end, a review of the literature was conducted in the main databases, auxiliary data sources, and official websites. Therefore, considering the hypercoagulability status of COVID-19, the debate about the use of contraceptives due to the relative risk of thromboembolic effects that they impose arises. However, the current available evidence, as well as the recommendations of main health organs around the world, demonstrate that the use of hormonal contraceptives must be maintained during the pandemic.
... In comparison with COC-levonorgestrel users, the incidence of VTE was slightly lower in users of E2V/dienogest and E2/nomegestrol acetate ( Table 3). This suggests that EE/levonorgestrel is not the only option for minimizing the risk of VTE associated with COC use, but estradiol-containing product is equally safe (86). This also reflects that those biological investigations may, at least in part, correlate with epidemiological data. ...
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Many factors must be considered and discussed with women when initiating a contraceptive method and the risk of venous thromboembolism (VTE) is one of them. In this review, we discuss the numerous strategies that have been implemented to reduce the thrombotic risk associated with combined oral contraceptives (COCs) from their arrival on the market until today. Evidences suggesting that COCs were associated with an increased risk of VTE appeared rapidly after their marketing. Identified as the main contributor of this risk, the dosage of the estrogen, i.e., ethinylestradiol (EE), was significantly reduced. New progestins were also synthetized (e.g., desogestrel or gestodene) but their weak androgenic activity did not permit to counterbalance the effect of EE as did the initial progestins such as levonorgestrel. Numerous studies assessed the impact of estroprogestative combinations on hemostasis and demonstrated that women under COC suffered from resistance towards activated protein C (APC). Subsequently, the European Medicines Agency updated its guidelines on clinical investigation of steroid contraceptives in which they recommended to assess this biological marker. In 2009, estradiol-containing COCs were marketed and the use of this natural form of estrogen was found to exert a weaker effect on the synthesis of hepatic proteins compared to EE. In this year 2021, a novel COC based on a native estrogen, i.e., estetrol, will be introduced on the market. Associated with drospirenone, this preparation demonstrated minor effects on coagulation proteins as compared with other drospirenone-containing COCs. At the present time, the standard of care when starting a contraception, consists of identifying the presence of hereditary thrombophilia solely on the basis of familial history of VTE. This strategy has however been reported as poorly predictive of hereditary thrombophilia. One rationale and affordable perspective which has already been considered in the past could be the implementation of a baseline screening of the prothrombotic state to provide health care professionals with objective data to support the prescription of the more appropriate contraceptive method. While this strategy was judged too expensive due to limited laboratory solutions, the endogenous thrombin potential-based APC resistance assay could now represent an interesting alternative.
... Hormone replacement therapy (HRT) and bisphosphonates are the primary therapeutic strategies for bone loss diseases including osteoporosis (He et al., 2017). Long-term HRT may significantly increase the risk of endometrial and mammary cancer, and coronary heart disease and other cardiovascular diseases (Dinger et al., 2016a;Dinger et al., 2016b). While bisphosphonates may lead to osteonecrosis of the long bones and jaws (Spivakovsky, 2017;Lungu et al., 2018). ...
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Osteoporosis is a bone disease characterized by increasing osseous fragility and fracture due to the reduced bone mass and microstructural degradation. Primary pharmacological strategies for the treatment of osteoporosis, hormone replacement treatment (HRT), and alendronate therapies may produce adverse side-effects and may not be recommended for long-term usage. Some classic and bone-specific natural Chinese medicine are very popularly used to treat osteoporosis and bone fracture effectively in clinical with their potential value in bone growth and development, but with few adverse side-effects. Current evidence suggests that the treatments appear to improve bone metabolism and attenuate the osteoporotic imbalance between bone formation and bone resorption at a cellular level by promoting osteoblast activity and inhibiting the effects of osteoclasts. The valuable therapies might, therefore, provide an effective and safer alternative to primary pharmacological strategies. Therefore, the purpose of this article is to comprehensively review these classic and bone-specific drugs in natural Chinese medicines for the treatment of osteoporosis that had been deeply and definitely studied and reported with both bone formation and antiresorption effects, including Gynochthodes officinalis (F.C.How) Razafim. & B.Bremer (syn. Morinda officinalis F.C.How), Curculigo orchioides Gaertn., Psoralea corylifolia (L.) Medik Eucommia ulmoides Oliv., Dipsacus inermis Wall. (syn. Dipsacus asperoides C.Y.Cheng & T.M.Ai), Cibotium barometz (L.) J. Sm., Velvet Antler, Cistanche deserticola Ma, Cuscuta chinensis Lam., Cnidium monnieri (L.) Cusson, Epimedium brevicornum Maxim, Pueraria montana (Lour.) Merr. and Salvia miltiorrhiza Bunge., thus providing evidence for the potential use of alternative Chinese medicine therapies to effectively treat osteoporosis.
... CHC containing the newer type of estrogen, i.e., estradiol, may be associated with a similar or even a lower risk on thrombosis compared with CHC containing levonorgestrel and ethinylestradiol [9][10][11]. ...
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Objectives We investigated combined hormonal contraceptives (CHC) prescribing patterns (focusing on combined oral contraceptives; COC) in three countries (Netherlands, Denmark, United Kingdom) in a time period preceding and in a time period following the European Commission's decision to update product information, and we estimated changes in incidence of venous thromboembolism (VTE) between the two periods. Study design We conducted a drug utilization analysis and a cohort study using routinely collected data. We calculated number, proportion and incidence rate of new users, switchers, and stoppers of COC in both time periods. VTE incidence was calculated in new users of COC and in all women aged 18–49 years. Results In all countries, the largest proportion (> 75%) of new users used COC containing levonorgestrel, norethisterone, or norgestimate, (i.e., indicated by European Medicines Agency (EMA) as the safest preparations) in both time periods. Switching did not demonstrate a clear pattern towards these types of COC and distribution of stoppers was similar in both time periods. While the proportion of new users initiating COC containing levonorgestrel, norethisterone, or norgestimate increased slightly, this did not translate to a decrease in the overall VTE incidence. Conclusion All three countries had the greatest proportion of women initiating a COC containing levonorgestrel, norethisterone, or norgestimate, and this proportion increased in the period after the European Commission decision albeit the increase was small due to the high percentage of use before the decision. This did not translate into a measureable change in the incidence of VTE. Implications Both before and after the European Commission's decision, the largest proportion of new users started with combined oral contraceptives containing levonorgestrel, norethisterone, or norgestimate. Earlier studies had already indicated an increased risk of VTE associated with COC containing other progestogens compared with these preparations, so it is possible that physicians were already preferentially prescribing COC containing levonorgestrel, norethisterone, or norgestimate to new users.
... Действительно, по сравнению с КОК, содержащими в своем составе ЭЭ, КОК с натуральным эстрогеном оказывает меньшее воздействие на суррогатные маркеры тромботического риска [34]. В 2016 г. были опубликованы результаты крупномасштабного проспективного контролируемого когортного исследования с активным наблюдением International Active Surveillance study «Safety of Contraceptives: Role of Estrogens» (INAS-SCORE; n=50 203), которое проводилось в США и 7 европейских странах с целью оценки сердечно-сосудистых рисков на фоне Э2В/ДНГ в сравнении с другими КОК, в частности с комбинацией ЭЭ/ЛНГ, наиболее изученной в отношении ВТЭ [35]. Первичный анализ европейских данных показал, что применение комбинации Э2В/ДНГ в течение 2-5 лет (в среднем в течение 2,1 года) сопровождалось более низким риском ВТЭ по сравнению с ЭЭ/ЛНГ и другими КОК (скорректированный относительный риск 0,4 и 0,5 соответственно). ...
Article
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Abnormal uterine bleeding (AUB) is one of the most common frequent reasons for contacting a gynecologist and conducting intrauterine interventions. AUB causes iron deficiency anemia and a decrease quality of life of women, which in turn is the reason of their social and clinical significance. Based on the analysis of literature and international data recommendations, the review outlines the basic principles of AUB diagnosis, non-hormonal and hormone therapy Advantages of continuous regimen for the administration of progestogens, in particular the LNG-IUS, and COCs containing estradiol valerate, to reduce menstrual flow blood loss are presented in the article. The need for a differentiated approach of choosing the therapy based on age, causes of bleeding, and balance benefits and risks of medicines.
Article
Introduction: Previously, the American College of Obstetrics and Gynecology (ACOG) had published an excellent practice bulletin addressing the use of hormone contraception in women with pre-existing medical conditions. This practice bulletin became out of date. The Centers for Disease Control and prevention (CDC) of the United States subsequently developed a point form guideline for the use of oral contraceptives in women with co-existing medical conditions. Evidence acquisition: Although this acts as a guide, it leaves the clinician without an understanding of why they are doing what they are doing. This article, is one of two related to women with co-existing medical conditions. Evidence synthesis: In this article we will provide an update of the scientific knowledge since the publication of the ACOG guideline (2006). It is to be used as a supplement for those who desire more information than is found in the CDC guidelines. Conclusions: Although some recommendations have remained unchanged over the years, the development of lower dose contraceptive pills as well as the increased incidence of comorbid conditions, such as metabolic syndrome, in younger women seeking contraception has brought along new research and new evidence to guide clinicians in the prescription of these medications.
Article
Objective: To evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism. Study Design We conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information. Results: Sixty-five participants enrolled in E2 75 (n=22), 100 (n=21), and 200 (n=22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4-5 of CVR use at 194 pg/mL (range 114-312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28-62 pg/mL) on days 88-90 (n=11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0-16) and three (range 0-19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days. Conclusions: Estradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use. Implications A 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.
Article
Hypertension is a major risk factor for cardiovascular diseases. Because of the high frequency of hormonal contraceptives use, assessing their side effects is an important public health issue. In this perspective, we conducted a review of the risk of hypertension associated with the use of hormonal contraceptives, either combined estrogen-progestin or only progestin. The use of combined hormonal contraceptives, regardless of its type and route of administration, is associated with a slight increase in blood pressure, both systolic and diastolic blood pressures. The frequency of onset of hypertension in women who use combined hormonal contraception is between 0.6% and 8.5%. Progestin-only contraception seems safe with respect to the risk of hypertension. It is therefore important to remember that the use of combined hormonal contraception is contra-indicated in hypertensive women, even well controlled. Finally, we propose a prescription assistance algorithm according to the recommendations of an expert panel. It should be remembered that taking blood pressure at each contraceptive consultation (initial and follow-up) is essential. Copyright © 2019 Elsevier Masson SAS. All rights reserved.
Article
Background: Most women of child-bearing age want a safe method of contraception. Numerous methods are available, with different modes of application. In situations involving particular risks, the selection of the right method poses a special challenge. Methods: Contraceptive methods for use in various situations with increased risk are presented in the light of a selective review of the literature, including the relevant current guidelines. Results: The current recommendations of the World Health Organization (WHO) can be used to determine whether any particular contraceptive method is applicable. In particular, the use of combined hormonal contraceptives may be contraindicated in the presence of certain risk factors, especially when there is an elevated risk of thromboembolism. Situations of increased risk include a genetic predisposition to thrombophilia, diabetes mellitus, age over 35, and nicotine abuse. Careful attention to the choice of an appropriate contraceptive agent is also necessary for women with hypertension, hepatic tumors, headache (including migraine), and epilepsy. For such patients, good alternatives include the use of a gestagen (=progesterone) single-agent preparation, an intrauterine device, or a pessary. Conclusion: Meticulous history-taking and clinical examination are important components of contraceptive counseling that enable the identification of all potential risk factors. In situations of increased risk, decisions must be taken individually. Depending on the nature of the patient's underlying illness, interdisciplinary collaboration may be advisable. Even in situations of increased risk, an appropriated risk-benefit analysis should make it possible to find a suitable contraceptive method for any woman who needs one.
Article
Eine Thrombophilie ist eine erworbene oder genetisch bedingte Neigung zur Bildung von venösen und/oder arteriellen Thrombosen. Dabei gehören die Faktor-V-Leiden-Mutation sowie die Prothrombinmutation G20210A zu den häufigsten hereditären Formen. Viele Träger einer genetisch bedingten Thrombophilie bleiben jedoch auch über Jahre asymptomatisch. Häufig führen erst ein oder mehrere weitere zusätzliche Risikofaktoren zur Auslösung eines Ereignisses. Ein wichtiger Faktor ist auch die hormonelle Kontrazeption, die von rund 140 Mio. Frauen weltweit zur Verhütung angewandt wird. Neben der Östrogenkomponente als wichtiger Faktor zur Steigerung des Thromboserisikos wird auch die Wahl des Gestagens als Risikofaktor diskutiert. Gestagenmonopräparate mit Ausnahme von Depotmedroxyprogesteronacetat (DMPA) steigern das Thromboserisiko nicht. Für den Fall einer Thrombophilie konnte unter Anwendung kombinierter hormoneller Kontrazeptiva ein Multiplikationseffekt hinsichtlich des Thromboserisikos nachgewiesen werden. Methode der Wahl bei bekannter Thrombophilie ist die Anwendung eines Intrauterinpessars oder auch reiner Gestagenpräparate (mit Ausnahme von DMPA).
Article
The risk of venous thrombosis (VT) varies according to the type of progestogen that is found in combined oral contraceptives (COCs). When combined with the estrogen component ethinylestradiol (EE), the androgenic progestogens are better able to counteract the EE-induced stimulation of liver proteins and hence are associated with a twofold decreased risk of VT compared with non- or antiandrogenic progestogens, which exert limited counteraction of EE. Because EE is responsible for the increased risk, novel estrogens such as estradiol were developed and seem to have a lower risk of VT than EE. Besides COCs, there are other methods of hormonal contraceptives, such as progestogen-only contraceptives, which do not increase VT risk, except for injectables. Other nonoral contraceptives are combined vaginal rings and patches. There is insufficient evidence regarding the risk of VT associated with these two methods compared with COCs. The increased risk associated with COCs is more pronounced in women with inherited thrombophilia. In these women, the progestogen levonorgestrel seems to be associated with the lowest risk of VT. Currently, there are no studies that have investigated the risk of VT in women who switch COCs. We hypothesize that switching COCs, even when switching from a high- to a low-risk COC, increases the risk of VT. Finally, risk prediction models in women who use COCs are lacking. Since there is a large number of VT cases associated with COC use, it is important to identify women at risk of VT and advise them on alternative contraception methods.
Article
Purpose of review: Combined oral contraceptive pills are among the most widely used contraceptive methods globally. Despite their popularity, the potential risks and side effects can lead to both high discontinuation rates and adverse outcomes including thromboembolic events. The quest for a safer alternative to the traditional ethinyl estradiol/progestin combination has led to the use of newer oestrogens. Ethinyl oestradiol alternatives will be reviewed including the newest option, estetrol, as it enters clinical use. Recent findings: Oestradiol, when combined with a progestin with strong endometrial activity, is a viable alternative to ethinyl estradiol in the form of oestradiol valerate and estradiol, which have been available since 2008 and 2011, respectively. Estetrol is the newest oestrogen available and is found naturally in the foetal liver. Estetrol was approved for use in 2021. All three of these alternatives have high contraceptive efficacy, similar if not improved cycle control and decreased impact on haemostatic factors as compared to ethinyl estradiol. Summary: Alternatives to ethinyl oestradiol, including the newest option of estetrol, show promise in providing comparable contraceptive efficacy with potentially lower risk of side effects and thromboembolic events.
Article
Zusammenfassung Hormonelle Kontrazeption und Thromboembolie-Risiko Kombinierte hormonelle Kontrazeptiva (KK) erhöhen das VTE-Risiko signifikant. Gestagen-Monopräparate sind mit Ausnahme der 3-Monatsspritze nicht mit einem erhöhten VTE-Risiko assoziiert und können bei Frauen mit vorausgegangener VTE oder thrombophilen Risikofaktoren mit Wunsch nach hormoneller Verhütung angewandt werden. Individuelle Risikofaktoren und hormonelle Kontrazeption Vor der Verschreibung einer hormonellen Kontrazeption soll eine sorgfältige Erhebung des VTE-Risikos erfolgen. Eine entsprechende Checkliste findet sich auf der Internetseite des BfArM. Eine routinemäßige Testung auf hereditäre Thrombophilie wird nicht empfohlen. Kontrazeption unter Antikoagulation Orale Antikoagulanzien sind plazentagängig und prinzipiell embryotoxisch und erfordern somit die Anwendung einer sicheren Empfängnisverhütung. Eine häufige Nebenwirkung unter oraler Antikoagulanzientherapie ist das Auftreten einer Hypermenorrhö. Die hormonelle Kontrazeption kann bei bestehender Antikoagulation auch mit einem Kombinationspräparat fortgeführt werden, sofern spätestens 6 Wochen vor Beendigung der Antikoagulation die Umstellung auf eine östrogenfreie Form der Kontrazeption erfolgt. Hormonassoziierte VTE und Rezidivrisiko VTE, die bei Frauen unter Verwendung von hormonellen Kontrazeptiva aufgetreten sind, gelten als provozierte Ereignisse. Das Rezidivrisiko einer hormonassoziierten VTE ist nach Absetzen der Antikoagulation und Umstellung auf eine östrogenfreie Form der Kontrazeption gering, sodass eine Antikoagulationsdauer von 3–6 Monaten in der Regel ausreichend ist. Nach hormonassoziierter VTE wird während einer künftigen Schwangerschaft und im Wochenbett eine medikamentöse VTE-Prophylaxe empfohlen.
Article
Context There are limited studies comparing the effects of combined oral contraceptives (COCs) containing natural estrogens and synthetic ethinylestradiol (EE) on reproductive hormones. Objective To compare estradiol valerate (EV)+dienogest (DNG), EE+DNG, and DNG alone (an active control) on levels of follicle stimulating hormone (FSH), luteinizing hormone, Anti-Müllerian hormone (AMH), ovarian steroids, sex hormone binding globulin (SHBG), and the Free Androgen Index (FAI). Design Spin-off study from a randomized trial. Setting Outpatient setting at Helsinki and Oulu University Hospitals, Finland. Participants 59 healthy, 18–35-year-old ovulatory women were enrolled. Three women discontinued. The groups were comparable as regards age and body mass index. Interventions EV 2mg+DNG 2–3mg (n=20), EE 0.03mg+DNG 2mg (n=20) and DNG 2mg (n=19) were used continuously for nine weeks. Blood samples were drawn at baseline, and at 5 and 9 weeks. Main Outcome Measures EV+DNG suppressed FSH by -27% (-51:-3) (median [95%CI]) vs. EE+DNG, -64% (-78: -51), P=0.04, but AMH levels decreased similarly by -9% (-18: -0.1) vs. -13% (-28:0.2), P=0.38, respectively. EV+DNG increased SHBG levels by 56% (30:82) and EE+DNG by 385% (313:423), P<0.001. Total testosterone (T) decreased by 16% (-27: -5) in the EV+DNG group but it did not decrease in the EE+DNG group, whereas the FAI decreased by -39% (-54: -25) vs. -72% (-78: -67), P<0.001. DNG alone did not induce changes in any of these parameters. Conclusions Compared with EE+DNG, treatment with EV+DNG resulted in milder pituitary downregulation and reduced induction of hepatic SHBG synthesis—potentially carrying more beneficial health effects.
Article
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Objective The present study aimed to understand patient perception of the adverse effects of contraceptives to improve health care and adherence to treatment. Methods An online questionnaire was available for women in Brazil to respond to assess their perception of adverse effects and their relationship with contraceptive methods. Results Of all 536 women who responded, 346 (64.6%) reported current contraceptive use. One hundred and twenty-two (122–34.8%) women reported having already stopped using contraception because of the adverse effects. As for the contraceptive method used, the most frequent was the combined oral contraceptive (212–39.6%). When we calculated the relative risk for headache, there was a relative risk of 2.1282 (1.3425–3.3739; 95% CI), suggesting that the use of pills increases the risk of headache, as well as edema, in which a relative risk of 1.4435 (1.0177–2.0474; 95% CI) was observed. For low libido, the use of oral hormonal contraceptives was also shown to be a risk factor since its relative risk was 1.8805 (1.3527–2.6142; 95% CI). As for acne, the use of hormonal contraceptives proved to be a protective factor, with a relative risk of 0.3015 (0.1789–0.5082; 95% CI). Conclusion The choice of a contraceptive method must always be individualized, and the patients must be equal participants in the process knowing the expected benefits and harms of each method and hormone, when present.
Article
The new coronavirus disease-19 (COVID-19) pandemic has rapidly spread all around the world, eliciting many questions and doubts about the pathogenesis of the disease and treatment. Mortality has been related to a prothrombotic state. Risk factors for the infection and for severe forms of COVID-19 have still to be defined. According to data collected, women appear to be less prone to severe forms of the disease and their mortality was lower than for men. The role of female hormones in the modulation of inflammation may be the reason behind this gender gap. Considering the prothrombotic state activated by the virus, hormone therapies have been placed under investigation as possible increasing risk factors for severe forms. Moreover, new vaccines and their rare thrombotic side effects have increased the concern about this issue. The goal of this review is to go over the mechanisms that lead up to thrombosis during COVID-19, trying to explain the possible reasons why women seem to be naturally protected. The expert opinions about whether to continue/discontinue hormonal therapies are reviewed. Moreover, available data about the so-called ‘vaccine induced immune thrombotic thrombocytopaenia’ caused by vaccines against COVID-19 are discussed.
Article
Background: Hormonal pills are among the most widely contraceptive methods used by women, despite the possible onset of different adverse events. To minimize the risk of thrombosis-related adverse events, different formulations and doses have been investigated. Micronized estradiol (E2)/nomegestrol acetate (NOMAC) 24+4 is the first monophasic combined oral contraceptive pill containing natural E2, the same steroid produced by the granulosa cells of women ovaries. This combination presents an improved effect on hemostasis and metabolism compared to ethinyl-estradiol (EE)-based products and may be considered a good option to meet women's needs in a more physiological way. Despite the benefits of E2, its use is still not so common among combined oral contraceptives (COC). Methods: Seventy-seven Italian gynecologists were involved and asked to answer a survey to investigate some aspects related to contraception. The results of the survey were discussed within the same gynecologists and a panel of experts during eight macro-regional meetings. Results: The survey demonstrated that clinicians dedicate 40-60% of their time to contraception and confirmed the importance of the choice of the contraceptive pill, which is mostly prescribed for contraceptive purposes. Moreover, COC containing E2 is considered as the first choice in oral contraception and meets the features of an ideal pill. Conclusions: Italian gynecologists reported that E2-based pill presents benefits related to safety, good tolerability, and low adverse events, in particular, related to a reduced thromboembolic risk. Research market data highlight that the use of these types of COC should expand with respect to traditional compounds containing EE.
Article
The use of combined hormonal contraceptives (CHC) increases not only the risk for venous thromboembolism, but also for arterial thromboembolism. The risk for thromboembolism is the same for non-oral CHC (patches, vaginal rings) as for oral CHC. Risk factors such as age > 35, obesity, smoking and a positive family history need to be recognized and considered in contraceptive counselling. Complete information concerning risks and benefits is mandatory. This applies for first-time as well as for long-term users. Careful investigation of the history is required, and the risk factors need to be re-evaluated at yearly prescription. It is also very important to inform patients regarding early symptoms of thrombosis or pulmonary embolism so that therapy can be immediately started. However, CHC not only have risks, but also for many women beneficial effects on organs such as the ovaries, on the endometrium as well as on general well-being. When prescribing a CHC for the first time or when changing to another preparation, one should always weigh up whether certain benefits justify prescribing a preparation with a slightly higher risk of thrombosis compared to the second-generation pill. Women that are already using a third-generation pill or a pill with drospirenone or cyproterone acetate and feel comfortable with it do not need to switch to another preparation (provided no new risk factors have arisen). For women with increased risks, i.e. several relative contraindications or one absolute contraindication, safe alternatives to CHC include progestogen-only preparations, intrauterine devices or, after family planning has been completed, surgical methods (sterilisation/vasectomy).
Article
Oral contraceptives are mainly used for birth control in Germany. The choice is between a combined oral contraception and a gestagen monotherapy. For combined oral contraception the estrogen component ethinyl estradiol is available in various doses in addition to estradiol. Furthermore, the selection of the optimal gestagen in the combination, plays a particularly important role in the clinical practice. In gestagen monotherapy there is also a choice between desogestrel and drospirenone. In general, the risk of venous thromboembolism is important for the combined oral contraception, whereas for special indications the partial effects of the individual gestagens should be considered in addition to the dosing of ethinyl estradiol. From this there are special advantages for the individual combined oral contraceptives as well as for gestagen monotherapy in different patients. Therefore, patients can benefit not only from a reliable contraception but also in many gynecological diseases from the additional effects of oral contraception. In this article the principles of decision guidance in the practice are presented and practical recommendations are given for 13 special situations based on scientific data.
Article
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The review presents the psychosocial characteristics of young women in todays millennial generation and survey data regarding their hormonal contraceptive requirements. The results of randomized clinical trials and real-life studies of the use of the combined oral contraceptive (COC) Qlaira containing estradiol valerate and dienogest (E2V/DNG) in a dynamic dosing regimen were analyzed, in which the reliability of the contraceptive effect of the drug was identified and confirmed, the restoration of fertility was population level after drug withdrawal, its minimal effect on metabolism and a reduced risk of cardiovascular complications (venous and arterial thrombosis) when using Qlaira COC in comparison with other COCs. The absence of a negative effect of COC E2V/DNG on body weight, sexual function and vaginal microbiocenosis in most women has been proven. The data on satisfactory characteristics of menstrual bleeding (lighter and shorter) in users of Qlaira COC and a decrease in symptoms associated with a hormone-free interval, which often occur when taking other COCs in the 21/7 regimen, are presented. The favorable efficacy and safety profile of COC E2V/DNG in real conditions, the advantages of estrogen bioidentical to the endogenous, in the composition of the drug, the dosage regimen 26/2, the positive effect on the lifestyle, determine the significant satisfaction of young women, including young women with children, and the ability to use the drug for a long time until menopause.
Article
Was ist neu? Hormonelle Kontrazeption und Thromboembolie-Risiko Kombinierte hormonelle Kontrazeptiva (KK) erhöhen das VTE-Risiko signifikant. Gestagen-Monopräparate sind mit Ausnahme der 3-Monatsspritze nicht mit einem erhöhten VTE-Risiko assoziiert und können bei Frauen mit vorausgegangener VTE oder thrombophilen Risikofaktoren mit Wunsch nach hormoneller Verhütung angewandt werden. Individuelle Risikofaktoren und hormonelle Kontrazeption Vor der Verschreibung einer hormonellen Kontrazeption soll eine sorgfältige Erhebung des VTE-Risikos erfolgen. Eine entsprechende Checkliste findet sich auf der Internetseite des BfArM. Eine routinemäßige Testung auf hereditäre Thrombophilie wird nicht empfohlen. Kontrazeption unter Antikoagulation Orale Antikoagulanzien sind plazentagängig und prinzipiell embryotoxisch und erfordern somit die Anwendung einer sicheren Empfängnisverhütung. Eine häufige Nebenwirkung unter oraler Antikoagulanzientherapie ist das Auftreten einer Hypermenorrhö. Die hormonelle Kontrazeption kann bei bestehender Antikoagulation auch mit einem Kombinationspräparat fortgeführt werden, sofern spätestens 6 Wochen vor Beendigung der Antikoagulation die Umstellung auf eine östrogenfreie Form der Kontrazeption erfolgt. Hormonassoziierte VTE und Rezidivrisiko VTE, die bei Frauen unter Verwendung von hormonellen Kontrazeptiva aufgetreten sind, gelten als provozierte Ereignisse. Das Rezidivrisiko einer hormonassoziierten VTE ist nach Absetzen der Antikoagulation und Umstellung auf eine östrogenfreie Form der Kontrazeption gering, sodass eine Antikoagulationsdauer von 3–6 Monaten in der Regel ausreichend ist. Nach hormonassoziierter VTE wird während einer künftigen Schwangerschaft und im Wochenbett eine medikamentöse VTE-Prophylaxe empfohlen.
Article
Background Several promising new medications containing low-dose estradiol (E2) in combination with a progestin and an additional component, such as gonadotropin-releasing hormone antagonists, are currently being developed for use in pre-menopausal women. Objective This pooled analysis was designed to estimate the thromboembolic safety profile of E2 and its ester, estradiol valerate (E2Val), when used in combined hormonal treatments in a pre-menopausal population. Methods Data regarding users of combined oral contraceptives (COCs) and combined menopausal hormonal therapy (MHT) containing either E2/E2Val or ethinylestradiol (EE) ⩽ 30 µg were retrieved from five large prospective, non-interventional, cohort studies in Europe, US, and Canada with similar study design but differing medication cohorts. Propensity score sub-classification was applied to balance baseline parameters between cohorts and time-to-event analysis of venous thromboembolic events (VTE) was carried out based on the extended Cox model to calculate crude and adjusted hazard ratios (HR). Results (1) Crude incidence rates of VTE were higher in MHT users compared to pre-menopausal COC users, (2) the VTE risk in menopausal users of E2/E2Val-norethindrone acetate was not higher than that in menopausal users of E2/E2Val-progestin (adjusted HR 0.71; 95% confidence interval, 0.41-1.26) and (3) the VTE risk in pre-menopausal users of E2/E2Val-progestin was similar, or lower, than pre-menopausal users of EE⩽30µg-progestin (adjusted HR 0.49; 95% confidence interval, 0.28–0.84). Conclusion Our data presents a solid safety assessment of combined hormonal preparations containing E2/E2Val. We conclude that the risk of E2/E2Val-norethindrone acetate in pre-menopausal users is unlikely to be higher than the known risk of COCs containing EE ⩽ 30 µg-progestin.
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Early loss of ovarian function can present insidiously with occasional periods of recovery. This occurs in the great majority of cases, and it should be identified as premature ovarian insufficiency (POI). Cases with sudden, definitive onset (due to bilateral ovariectomy or treatments usually related to oncological conditions) should be considered premature ovarian failure (POF). Therapy aims at treating hormone deficits and other underlying causes. POI symptoms include the classic short-term ones (vasomotor symptoms, insomnia, joint pain, mood changes, low energy and low libido, impaired memory, and concentration difficulties) as well as various repercussions on the lower genital tract, the cardiovascular system, bone mass (osteopenia, osteoporosis, increased fracture risk, arthrosis), cognitive function (cognitive dysfunction, especially memory and concentration problems, plus increased risk of dementia), mood, and loss of reproductive capacity.
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A positive family history of venous thrombosis may reflect the presence of genetic risk factors. Once a risk factor has been identified, it is not known whether family history is of additional value in predicting an individual's risk. We studied the contribution of family history to the risk of venous thrombosis in relation to known risk factors. In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis, a population-based case-control study, we collected blood samples and information about family history and environmental triggers from 1605 patients with a first venous thrombosis and 2159 control subjects. A total of 505 patients (31.5%) and 373 controls (17.3%) reported having 1 or more first-degree relatives with a history of venous thrombosis. A positive family history increased the risk of venous thrombosis more than 2-fold (odds ratio [95% confidence interval], 2.2 [1.9-2.6]) and up to 4-fold (3.9 [2.7-5.7]) when more than 1 relative was affected. Family history corresponded poorly with known genetic risk factors. Both in those with and without genetic or environmental risk factors, family history remained associated with venous thrombosis. The risk increased with the number of factors identified; for those with a genetic and environmental risk factor and a positive family history, the risk was about 64-fold higher than for those with no known risk factor and a negative family history. Family history is a risk indicator for a first venous thrombosis, regardless of the other risk factors identified. In clinical practice, family history may be more useful for risk assessment than thrombophilia testing.
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The true frequency of deep-vein thrombosis (DVT) during long-haul air travel is unknown. We sought to determine the frequency of DVT in the lower limb during long-haul economy-class air travel and the efficacy of graduated elastic compression stockings in its prevention. We recruited 89 male and 142 female passengers over 50 years of age with no history of thromboembolic problems. Passengers were randomly allocated to one of two groups: one group wore class-I below-knee graduated elastic compression stockings, the other group did not. All the passengers made journeys lasting more than 8 h per flight (median total duration 24 h), returning to the UK within 6 weeks. Duplex ultrasonography was used to assess the deep veins before and after travel. Blood samples were analysed for two specific common gene mutations, factor V Leiden (FVL) and prothrombin G20210A (PGM), which predispose to venous thromboembolism. Asensitive D-dimer assay was used to screen for the development of recent thrombosis. 12/116 passengers (10%; 95% CI 4.8-16.0%) developed symptomless DVT in the calf (five men, seven women). None of these passengers wore elastic compression stockings, and two were heterozygous for FVL. Four further patients who wore elastic compression stockings, had varicose veins and developed superficial thrombophlebitis. One of these passengers was heterozygous for both FVL and PGM. None of the passengers who wore class-I compression stockings developed DVT (95% CI 0-3.2%). We conclude that symptomless DVT might occur in up to 10% of long-haul airline travellers. Wearing of elastic compression stockings during long-haul air travel is associated with a reduction in symptomless DVT.
Article
Objectives: The "Long-term Active Surveillance Study for Oral Contraceptives" investigated the risks of long-term use of a 21-day regimen of drospirenone and ethinylestradiol (DRSP) compared to established oral contraceptives (OCs) in a routine clinical setting. Study design: Prospective, controlled, non-interventional cohort study conducted in seven European countries with three main exposure groups: new users of DRSP, levonorgestrel-containing OCs (LNG), and OCs containing other progestogens (Other OCs). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular cardiovascular events. Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Results: A total of 1,113 study centers enrolled 59,510 women. Overall 28%, 26% and 45% of these women used DRSP, LNG and Other OCs, respectively. Study participants were followed for up to ten years (mean value, 5.4 years), which generated 318,784 woman-years (WY) of observation. Low loss to follow-up and drop-out rates of 2.9% and 16.8% were achieved. DRSP, LNG, and Other OCs showed similar incidence rates of venous thromboembolism. Corresponding hazard ratios (HRs) were close to unity. For arterial thromboembolic events (ATE) and initiation of antihypertensive treatment statistically significant lower risks were found for DRSP compared to LNG and Other OCs. Conclusion: DRSP use was associated with similar general health risks and a low risk of ATE compared to OCs containing other progestogens. Implication statement: The 21-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risk of VTE compared to other combined oral contraceptives as well as potentially with a lower risk of ATE.
Article
Objectives: The menstrual cycle is characterised by cyclical fluctuations in oestrogens, progesterone and androgens. Changes in hormone levels in the premenstrual phase with the decline in progesterone trigger a physiological reaction which culminates in menstruation. This process is accompanied in many women by various symptoms such as pelvic pain, headache, mood disorders and gastrointestinal discomfort. The aim of this article was to summarise the latest findings on the physiology and pathophysiology of menstruation and review the impact of shortening the hormone-free interval (HFI) on the health and wellbeing of women. Results: Menstruation can be viewed as an inflammatory event in which local and systemic effects produce symptoms in genital and extragenital regions of the body. The mast cells are the main mediator of this reaction. In women using hormonal contraceptives, menstrual bleeding is not biologically necessary and it may be advantageous to maintain more stable levels of oestrogens, progesterone and androgens throughout the cycle. New combined oral contraceptives (COCs) have been formulated with a progressively shorter HFI (24/4 and 26/2) than traditional 21/7 pills, with the rationale of reducing hormone withdrawal- associated symptoms. Several studies have shown the beneficial effects of these regimens, which reduce the inflammatory exposure of the female organism and thus have the capacity to increase the quality of life of women. A combination of estradiol valerate (E2V) and dienogest (DNG) is administered on the shortest 26/2 regimen. This regimen has a broad evidence base from randomised controlled trials that have examined the impact of E2V/DNG on symptoms and quality of life. Conclusions: Shortening the HFI reduces the occurrence of bleeding-related inflammatory processes and subsequent physical and mental symptoms. The shortest interval with evidence of reproductive and sexual health benefits is provided by a 26/2 regimen.
Article
Objectives The ‘International Active Surveillance Study of Women Taking Oral Contraceptives’ (INAS-OC) investigated the risks of short and long-term use of an extended 24-day regimen of drospirenone and ethinylestradiol (DRSP24d) compared to established oral contraceptives (OCs) in a routine clinical setting. Study Design Prospective, controlled, non-interventional cohort study conducted in the USA and 6 European countries with three main cohorts: new users of DRSP24d, DRSP21d (21-day regimens of DRSP-containing OCs), and Non-DRSP (OCs without DRSP). All self-reported clinical outcomes of interest (OoI) were validated via attending physicians and relevant source documents. Main OoI were serious clinical outcomes, in particular venous thromboembolism (VTE). Comprehensive follow-up procedures were implemented. Statistical analyses were based on Cox regression models. Primary statistical variable was the VTE hazard ratio (HR) for DRSP24d versus Non-DRSP. Results A total of 2,285 study centers enrolled 85,109 women. Study participants were followed for two to six years, which generated 206,296 woman-years (WY) of observation. A low loss to follow-up of 3.3% was achieved. DRSP24d, DRSP21d, Non-DRSP and LNG (levonorgestrel-containing OCs) showed similar incidence rates of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events. VTE incidence rates for DRSP24d, DRSP21d, Non-DRSP, and LNG were 7.2, 9.4, 9.6, and 9.8 VTE/10,000 WY, respectively. Adjusted HRs for DRSP24d versus Non-DRSP and DRSP24d versus LNG were 0.8 (95% CI, 0.5-1.3) and 0.8 (95% CI, 0.4-1.5). Conclusion DRSP24d, DRSP21d, Non-DRSP, and LNG use was associated with similar risks of serious adverse events, and particularly VTE, during routine clinical use. Implication Statement The 24-day regimen of drospirenone-containing combined oral contraceptives is associated with similar risks of venous and arterial thromboembolism, fatal outcomes, cancer, severe depression and other serious adverse events compared to 21-day regimens of drospirenone-containing combined oral contraceptives, oral contraceptives without drospirenone, and levonorgestrel-containing oral contraceptives.
Article
Background: This study investigated the efficacy and safety of a combined oral contraceptive (COC) containing estradiol valerate/dienogest (E2V/DNG). Methods: This was a multicenter, noncomparative, 13-cycle (extended to 28 cycles) study conducted in the United States and Canada. Contraceptive efficacy was calculated as a Pearl Index for 13 cycles, based on all on-treatment pregnancies; bleeding patterns were calculated based on bleeding and spotting information recorded daily in diary cards. Safety events during a 16-month extension study were added to the 1-year data. Results: In total, 499 women, aged 18-35 years, were enrolled, and 490 of them were included in the full analysis set for contraceptive efficacy. Five pregnancies occurred in the first year (unadjusted Pearl Index=1.64). In cycles 1-12, an average 23.5% of women had absent scheduled (withdrawal) bleeding. Among women with scheduled (withdrawal) bleeding, bleeding started after a median of 2 days after intake of the last DNG-containing pill. For safety, data included from 147 women followed over an additional 16 months were added to the original 13-cycle data set. Treatment-related adverse events (AEs) occurred in 51.8% of women; 14.9% discontinued because of AEs over the entire 28-month study period. Conclusion: A COC with E2V and DNG was shown to provide effective contraception in women aged 18-35 years in North America.
Article
To compare the risks of short-term and long-term use of an etonogestrel-containing and ethinylestradiol-containing vaginal ring and combined oral contraceptive pills (OCPs) in a routine clinical study population. This was a prospective, controlled, noninterventional cohort study performed in the United States and five European countries with the following two cohorts: new users of the vaginal ring and new users of combined OCPs (starters, switchers, or restarters). The study population included 33,295 users of the vaginal ring or combined OCPs recruited by 1,661 study centers. Follow-up of study participants occurred for 2 to 4 years. Main clinical outcomes of interest were cardiovascular outcomes, particularly venous and arterial thromboembolism. These outcomes were validated by attending physicians and further adjudicated by an independent board. Comprehensive follow-up ensured low loss to follow-up. Statistical analyses were based on Cox regression models. Primary statistical variable was the venous thromboembolic hazard ratio (HR) for the vaginal ring compared with combined OCPs. Study participants were followed-up for 66,489 woman-years. Loss to follow-up was 2.9%. The venous thromboembolism incidence rates for the vaginal ring users and combined OCPs users were 8.3 and 9.2 per 10,000 woman-years, respectively. Cox regression analysis yielded crude and adjusted HRs for the vaginal ring users compared with combined OCPs users of 0.9 and 0.8 for venous thromboembolism (95% confidence intervals [CIs] 0.5-1.6 and 0.5-1.5) and 0.8 and 0.7 (95% CIs 0.2-2.5 and 0.2-2.3) for arterial thromboembolism, respectively. Vaginal ring use and combined OCP use were associated with a similar venous and arterial thromboembolic risk during routine clinical use. LEVEL OF EVIDENCE:: II.
Article
Epidemiological studies of suspected human teratogens not infrequently lead to recurring weak or moderate associations (relative risks or odds ratios ranging from greater than 1 to 3 for adverse effects and from 1/3 to less than 1 for protective effects) between specific defects and prenatal exposures. Examples of such associations include cigarette smoking and oral clefts (odds ratios between 1 and 2) and periconceptional multivitamin/folic acid supplementation and neural tube defects (odds ratios from 1/3 to 1). In this paper, we illustrate that low relative risk recurring in well-designed studies may reflect underlying biologic mechanisms and should not be readily dismissed. Low relative risks could be the result of a combination of the following factors: 1) unmeasured confounding, 2) exposure misclassification (often related to the inability to pinpoint relevant dose and timing), 3) outcome misclassification (related to the etiologic heterogeneity of birth defects), 4) biologic interactions (related to teratogenic effects in population subgroups defined by genetic susceptibility or the presence of other exposures), and 5) differential prenatal survival (related to the combined impact of the exposure and the defect on prenatal survival). These issues can be addressed in epidemiologic studies by using biological markers of exposure and susceptibility, dysmorphologic evaluation of affected infants, subgroup analysis for etiologic heterogeneity, a search for biologic interactions, and the use of prospective cohort studies. Finally, low relative risks in the face of common exposures can reflect an important public health contribution of the exposure to the occurrence of the defect in the population.
Article
In this paper, criteria used by many epidemiologists as aids in causal inference are reviewed and revised. The revised scheme emphasizes the distinction between essential properties of a cause and criteria useful for deciding on the presence of these properties in a given case. A systematic procedure for causal inference tests each essential causal property in turn against appropriate criteria. For a pragmatic epidemiology in which all determinants serve as causes, their essential properties are held to be association, time order, and direction, in an ascending hierarchy. Criteria for association are probabilistic and can be enhanced by strength and consistency. Given association, criteria for time order of the relevant variables follow from access to observation, which is dependent on design. Given association and time order, causal direction (or consequential change) calls on an array of criteria, namely, consistency and survivability, strength, specificity in cause and in effect, predictive performance, and coherence in all its forms (e.g., theoretical, factual, biologic, and statistical). The evolution of such criteria is traced through the epidemiologic literature in the light of historical context. Although Popper's philosophy cannot directly serve an inherently inductive judgmental process, his notion of survivability has here been added, alongside replicability, as a subclass of consistency. This criterion is proposed to bridge the gap between the particularity of designs and the generality required of causal relations. Designs are ordered and described in the framework of testing survivability. Finally, definitions are offered for the list of criteria deployed.
Article
The strength of a causal association depends on the relative prevalence of other component causes for the same disease. Weak associations may sometimes be strengthened by restricting attention to people at low risk. This technique may lead to fewer subjects to study, but nevertheless may provide more information by which to evaluate a causal relation. A second method for strengthening associations is to reduce non-differential misclassification, which tends to dilute associations. Increasing the specificity of measurement for exposure, disease, and the timing between causal action and disease onset should produce stronger associations that are easier to interpret and more descriptive of the underlying causal mechanism.
Article
The risk for venous thromboembolism after long-haul flights represents a controversial issue. The aim of our study was to assess the incidence of venous thrombosis associated with long-haul flights in a prospective, controlled cohort study. We included 964 passengers returning from long-haul flights (flight duration, > or =8 hours) and 1213 nontraveling control subjects. We excluded participants who were being treated with anticoagulant drugs or who used compression stockings. Main outcome measures were the incidence of ultrasonographically diagnosed thrombosis in the calf muscle and deep veins, symptomatic pulmonary embolism, and death. We diagnosed venous thrombotic events in 27 passengers (2.8%) and 12 controls (1.0%) (risk ratio [RR], 2.83; 95% confidence interval [CI], 1.46-5.49). Of these, 20 passengers (2.1%) and 10 controls (0.8%) presented with isolated calf muscle venous thrombosis (RR, 2.52; 95% CI, 1.20-5.26), whereas 7 passengers (0.7%) and 2 controls (0.2%) presented with deep venous thrombosis (RR, 4.40; 95% CI, 1.04-18.62). Symptomatic pulmonary embolism was diagnosed in 1 passenger with deep venous thrombosis (P =.44). All of these individuals had normal findings at baseline ultrasonography. Passengers with isolated calf muscle venous thrombosis or deep venous thrombosis had at least 1 risk factor for venous thrombosis (>45 years of age or elevated body mass index in 21 of 27 passengers). The follow-up after 4 weeks revealed no further venous thromboembolic event. Long-haul flights of 8 hours and longer double the risk for isolated calf muscle venous thrombosis. This translates into an increased risk for deep venous thrombosis as well. In our study, flight-associated thrombosis occurred exclusively in passengers with well-established risk factors for venous thrombosis.
Article
This is the first double-blind, controlled, randomized study comparing the effect of different estrogen components in oral contraceptives (OCs) on hemostasis variables. Four groups of 25 women each were treated for six cycles with monophasic combinations containing 21 tablets with either 30 microg ethinylestradiol (EE) + 2 mg dienogest (DNG) (30EE/DNG), 20 microg EE + 2 mg DNG (20EE/DNG), 10 microg EE + 2 mg estradiol valerate (EV) + 2 mg DNG (EE/EV/DNG) or 20 microg EE + 100 microg levonorgestrel (LNG) (EE/LNG). Blood samples were taken on Days 21-26 of the control cycle and on Days 18-21 of the first, third and sixth treatment cycle. Treatment with all four OCs caused an increase in levels of fibrinogen, prothrombin fragment 1+2, D-dimer, plasminogen, plasmin-antiplasmin complex and an increase in protein C activity, a decrease in antithrombin activity, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI), and a slight decrease in the sensitivity to activated protein C, but no significant change in that of the thrombin-antithrombin complex. In users of the DNG-containing OCs, the reduction in total and free protein S, and in t-PA and PAI was dependent on the EE dose, while factor VII activity was elevated, but not significantly different from EE/LNG. The results are in agreement with those of previous studies. The effects of EE/EV/DNG on total and free protein S and on t-PA and PAI were lower than those of 20EE/DNG, suggesting that the impact of 2 mg EV on several hemostasis variables is less than that of 10 microg EE. The results show an antagonistic effect of LNG on the EE-induced rise of factor VII activity and fragment 1+2 and on the EE-dependent reduction of total and free protein S.
Article
The study was conducted to compare risks of adverse cardiovascular and other events associated with the use of drospirenone (DRSP)-containing oral contraceptives (OCs) and other OCs. The European Active Surveillance study (EURAS) was a multinational, prospective, noninterventional cohort study of new users of DRSP, levonorgestrel (LNG) and other progestin-containing OCs. Semiannual follow-up was based on mailed questionnaires, with additional follow-up procedures when needed. Overall, 58,674 women were followed for 142,475 women-years of observation. Loss to follow-up was 2.4%. Serious adverse and fatal events were rare, and rate ratios were close to unity (1.0). Cox regression analysis of cardiovascular outcomes yielded hazard ratios for DRSP-containing vs. LNG-containing and other OCs of 1.0 and 0.8 (upper 95% confidence limits, 1.8 and 1.3) for venous, and 0.3 and 0.3 (upper 95% confidence limits, 1.2 and 1.5) for arterial thromboembolism, respectively. Risks of adverse cardiovascular and other serious events in users of a DRSP-containing OC are similar to those associated with the use of other OCs.