Progestin-only contraception and venous thromboembolism

doi:10.1016/j.thromres.2012.02.042

Thrombosis Research

Volume 129, Issue 5, May 2012, Pages e257-e262

https://doi.org/10.1016/j.thromres.2012.02.042 Get rights and content

Abstract

Combined oral contraceptives (COC) are the most popular contraceptive method in developed countries. Since their introduction there have been numerous changes and modifications in its composition with the aim to improve safety and tolerability while maintaining contraceptive efficacy. Most of the changes have been conducted on the progestin component, since most of the combinations include ethinyl estradiol as oestrogen. One of the adverse effects of COC is the increased risk of venous thromboembolism (VTE) in two clinical forms of presentation: deep vein thrombosis or pulmonary embolism. This review details the changes in haemostasis induced by progestin-only contraceptives and the risk of VTE in women who utilize this type of contraception; the relationship with other risk factors such as thrombophilia; the interactions of these contraceptives with anticoagulant treatment and finally the eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers.

Introduction

Combined oral contraceptive (COC) is the most popular contraceptive method in developed countries [1]. The basic mechanism of action of COCs is inhibition of ovulation due to the suppression of the activity of the hypothalamic-pituitary-ovary axis [2]. The progestin component of the COC exerts a negative feedback effect on the hypothalamic-pituitary function, resulting in an inhibition of luteinizing hormone secretion as well as its pre ovulatory peak, required to produce ovulation [3]. On the other hand, the oestrogen component inhibits the release of follicle stimulating hormone and consequently prevents follicle development [4].

Since the introduction of the first COC 50 years ago, there have been numerous changes and modifications in its composition with the aim to improve safety and tolerability while maintaining contraceptive efficacy. Most of the changes have been conducted on the progestin component, since most of the combinations include ethinyl estradiol (EE) as oestrogen. The primary aim of the oestrogen is to provide adequate cycle control and to allow the woman to have regular cycles [5].

Progestins can be classified according to the steroid hormone from which they derive namely testosterone, progesterone, or spironolactone (Table 1). The most commonly used progestins in contraception have been derived from testosterone. The first one, norethynodrel or norethisterone, was synthesized in 1954. The replacement of the methyl group in position 18 of norethisterone by an ethinyl group led to the synthesis of norgestrel, a powerful progestin belonging to the gonane group whose activity lies in its isomer, levonorgestrel [6].

Endogenous progesterone that is synthesized in the ovarian corpus luteum has antioestrogenic, antiandrogenic and anti-mineral corticoid properties. Thus, the synthesized progestins used for contraception have attempted to imitate these properties [7]. Besides the COC there are other contraceptives that contain progestin alone which are particularly suitable for women who have contraindications or intolerance to oestrogens or who want to avoid the use of oestrogens for different reasons.

One of the adverse effects of COC is the increased risk of venous thromboembolism (VTE) in two clinical forms of presentation: deep vein thrombosis or pulmonary embolism. The incidence of VTE increases with age but is rare among women of reproductive age (0.5-1 per 10,000 women per year) [8]. However, the use of COC is the most common risk factor of VTE among childbearing women [9]. It is estimated that the use of COC increases two to three times the risk of VTE, although the absolute risk is low. In addition, it is also important to note that these rates for the background incidence are clearly higher than the reference figures that are often utilized in the comparison with users of COC, according to a review of recent population studies [10]. With the current clinical criteria and diagnostic tools available (Doppler ultrasound and D-dimer) it has been shown that the incidence of VTE, among women not using COC as well as non-pregnant women is higher than estimated, being around 91-104/100,000 women/year [10].

This review details the changes in haemostasis induced by progestin-only contraceptives and the risk of VTE in women who utilize this type of contraception; the relationship with other risk factors such as thrombophilia; the interactions of these contraceptives with anticoagulant treatment and finally the eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers.

Section snippets

Progestin-only hormonal contraceptives and coagulation

COC produce a hypercoagulable state with increased fibrin production, due to significant changes in both procoagulant proteins as well as in the natural anticoagulants. The main reason of these changes is the oestrogen component of the contraceptive while progestins counteract such action to different degrees depending on the type of progestin [11], [12]. The most important effect of oestrogen on coagulation factors is the induction of acquired resistance to activated protein C.

Hormonal

Progestin-only hormonal contraceptives and risk of VTE

The risk of VTE is increased in users of combined hormonal contraceptives [21]. Every year 10,000 women of childbearing age suffer a venous thromboembolic disease, and this incidence is increased threefold to fivefold in women who use hormonal contraceptives [22]. Although the absolute risk is low, this type of contraception remains the most important factor for the development of VTE in women at fertile age, and in most cases, it remains the only factor that triggers the disease [9]. The

Progestin-only hormonal contraceptives and thrombophilia

Since the mid-1960's several inherited and acquired haemostasis disorders, also known as thrombophilias, have been associated with an increased risk of VTE. They are what is known as thrombophilias (Table 2) [37]. Although the different thrombophilias have similar clinical manifestations, they differ significantly in their frequency and severity (heterogeneity in clinical expression, see Table 3). For a given thrombophilia, the risk may vary among different families and even among members of

Progestin-only hormonal contraceptives and anticoagulation

There are no current studies that analyze the advantages or disadvantages of hormonal contraception in women receiving chronic anticoagulation for VTE. Most available data on contraceptive use in anticoagulated women are drawn from studies where they are used to treat the bleeding side effects due to anticoagulant therapy, such as menorrhagia or bleeding corpus luteum. In a study conducted by Pisoni et al. that assessed the efficacy and safety of the the implementation of a levonorgestrel IUD

Eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers

Most women of childbearing age could use any contraceptive method without any restrictions as they are young and generally healthy. However, there is a group of women who, due to certain pre-existing conditions, may be exposed to a risk with the use of certain contraceptive methods.

Therefore, the World Health Organization (WHO) has established a series of categories based on the possible health impact of using each of the available contraceptive methods (Table 5) [53]. The latest edition of

Conclusions

Progestins, in general, do not induce adverse changes in haemostasis factors. Since the prothrombotic effect is a consequence of the oestrogen, progestin-only preparations may be a good alternative for contraception in women in whom oestrogen use is contraindicated, such as those at high risk of VTE. The majority of the currently available studies that have analyzed the risk of VTE associated with progestin-only contraception have not shown a significantly increased risk of VTE. According with

Conflict of interest statement

The authors declare no potential conflicts of interest.

Acknowledgements

Editorial support was provided by Pipeline Biomedical Resources

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Cited by (33)

Female hormonal contraception
2018, Encyclopedia of Endocrine Diseases
Since the early 1960s, hormonal contraceptives have drastically changed, contemporary combined hormonal contraceptives (CHC) delivering 50–15 µg per day of EE or 1–3 mg of estradiol associated with newer progestogen. Moreover, it is important to distinguish combined hormonal contraceptives and progestin only contraceptive (POC), each with their indications, contraindications and potential side effects. The ideal contraception should be totally effective, acceptable, perfectly well tolerated, while preserving the subsequent fertility. But, such contraception does not exist. Indeed, the main deleterious effect of combined estrogen/progestin contraception remains vascular effects, principally venous thromboembolism event. The impact on the risk of cancer is either protective (ovarian, endometrial, colorectal) or deleterious (breast cancer). Finally, noncontraceptive benefits are important in some clinical circumstances. The choice of contraceptive method suitable for each woman is possible given the wide choice of hormonal contraceptives available. The WHO publication of the medical eligibility criteria for contraception use allows help for the prescription of contraception in various clinical situations.
Progestin-only contraception and thromboembolism: A systematic review
2016, Contraception
Citation Excerpt :
The risk of VTE among postpartum women is 2.5–84 times higher than that among nonpregnant nonpostpartum women [40]. Certain inherited conditions, such as antithrombin deficiency, protein C deficiency, protein S deficiency and FVL, confer a relative risk for VTE of 5–15 times higher compared with individuals without the condition [41]. Individuals with systemic lupus erythematosus have 3–8 times higher risk of VTE and individuals with inflammatory bowel disease have 3–4 times higher risk [42].
Women with medical conditions associated with increased risk for thrombosis generally should not use estrogen-containing contraceptives; however, less is known about progestin-only contraceptives (POCs) and thrombosis risk.
The objective was to identify evidence regarding the risk of venous thromboembolism (VTE) or arterial thromboembolism [stroke or acute myocardial infarction (AMI)] among women using POCs.
We searched the PubMed database for all articles published from database inception through January 2016 for studies examining thrombosis among women using POCs. We included studies which examined women with medical conditions associated with thrombosis risk, as well as studies of women in the general population (either without these conditions or who were not specified to have these conditions). Hormonal contraceptives of interest included progestin-only pills (POPs), injectables, implants and levonorgestrel-releasing intrauterine devices (LNG-IUDs). Outcomes of interest included VTE, stroke and AMI.
There were 26 articles of good to poor quality that met inclusion criteria; 9 studies examined women with medical conditions and 20 examined women in the general population. Two studies found that, among smokers and women with certain thrombogenic mutations, use of depot medroxyprogesterone acetate (DMPA) had elevated odds of VTE compared with nonsmokers or those without mutations, although confidence intervals were wide and overlapped with odds among nonusers. One study found that, among women with previous VTE, use of POCs (including DMPA) was associated with a nonsignificant increased odds of recurrent VTE (all of which were among DMPA users); two other studies that examined POCs other than DMPA did not observe an association with recurrent VTE. Two studies found that use of DMPA among healthy women was also associated with increased odds of VTE. Two studies found that use of POCs for therapeutic indications was associated with increased odds of VTE. Studies did not find increased odds of VTE with POPs for contraceptive purposes, implants or LNG-IUDs nor were there increased odds of stroke or AMI with any POCs.
The majority of evidence identified by this systematic review did not suggest an increase in odds for venous or arterial events with use of most POCs. Limited evidence suggested increased odds of VTE with use of injectables (three studies) and use of POCs for therapeutic indications (two studies, one with POCs unspecified and the other with POPs). Any increase in risk likely translates to a small increase in absolute numbers of thrombotic events at the population level.
Canadian Contraception Consensus (part 3 of 4): Chapter 8 - Progestin-only contraception
2016, Journal of Obstetrics and Gynaecology Canada
Fournir des lignes directrices aux fournisseurs de soins quant à l’utilisation de modes de contraception pour la prévention de la grossesse et quant à la promotion d’une sexualité saine.
Orientation des praticiens canadiens en ce qui concerne l’efficacité globale, le mécanisme d’action, les indications, les contre-indications, les avantages n’étant pas liés à la contraception, les effets indésirables, les risques et le protocole de mise en œuvre des modes de contraception abordés; planification familiale dans le contexte de la santé sexuelle et du bien-être général; méthodes de counseling en matière de contraception; et accessibilité et disponibilité des modes de contraception abordés au Canada.
La littérature publiée a été récupérée par l’intermédiaire de recherches menées dans MEDLINE et The Cochrane Library entre janvier 1994 et janvier 2015 au moyen d’un vocabulaire contrôlé (p. ex. contraception, sexuality, sexual health) et de mots clés (p. ex. contraception, family planning, hormonal contraception, emergency contraception) appropriés. Les résultats ont été restreints aux analyses systématiques, aux études observationnelles et aux essais comparatifs randomisés / essais cliniques comparatifs publiés en anglais entre janvier 1994 et janvier 2015. Les recherches ont été mises à jour de façon régulière et intégrées à la directive clinique jusqu’en juin 2015. La littérature grise (non publiée) a été identifiée par l’intermédiaire de recherches menées dans les sites Web d’organismes s’intéressant à l’évaluation des technologies dans le domaine de la santé et d’organismes connexes, dans des collections de directives cliniques, dans des registres d’essais cliniques et auprès de sociétés de spécialité médicale nationales et internationales.
La qualité des résultats a été évaluée au moyen des critères décrits dans le rapport du Groupe d’étude canadien sur les soins de santé préventifs (Tableau 1).
Déclarations sommaires
- 15.
  Les implants de progestatif comptent des taux d’échec aussi faibles que ceux de la contraception permanente. (II-2)
- 16.
  L’insertion d’un implant immédiatement à la suite d’un accouchement ou d’un avortement constitue une façon efficace d’abaisser les taux de nouvelle grossesse chez les adolescentes et de nouvel avortement. (II-2)
- 17.
  Les perturbations du cycle menstruel constituent l’effet indésirable le plus courant des modes de contraception à progestatif seul. (II-2) L’aménorrhée est très courante dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard et d’implants de progestatif. (II-2)
- 18.
  L’utilisation de progestatifs administrés selon des doses contraceptives ne semble pas accroître le risque de thromboembolie veineuse, d’infarctus du myocarde ou d’accident vasculaire cérébral. (II-2)
- 19.
  L’efficacité des implants de progestatif (ou de l’acétate de médroxyprogestérone) n’est pas amoindrie chez les femmes obèses ou présentant une surcharge pondérale. (II-2)
- 20.
  La constatation d’un gain pondéral précoce dans le cadre de l’utilisation d’acétate de médroxyprogestérone-retard permet de prédire la poursuite du gain pondéral. (II-2)
- 21.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à un délai quant à la reprise de l’ovulation. (II-2)
- 22.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse de la densité minérale osseuse. Cette baisse atteint sa rapidité maximale au cours des deux premières années d’utilisation et semble être largement réversible à la suite de l’abandon du traitement à l’acétate de médroxyprogestérone-retard. (I) Nous ne disposons pas de données probantes solides indiquant que l’utilisation d’acétate de médroxyprogestérone-retard cause l’ostéoporose (II-2) ou qu’elle entraîne une hausse du risque de fracture. (II-2)
- 23.
  Il n’a pas été démontré que l’utilisation de préparations à progestatif seul entraîne une baisse de la production de lait maternel. (I) Les petites quantités d’hormones stéroïdiennes sécrétées dans le lait maternel n’exercent pas un effet indésirable sur la croissance et le développement du nouveau-né. (II-2)
- 24.
  L’utilisation d’acétate de médroxyprogestérone-retard est associée à une baisse des risques de cancer de l’endomètre et de cancer de l’ovaire. (II-2)
Recommandations
- 12.
  Le recours à des modes de contraception à progestatif seul devrait être envisagé chez les femmes qui présentent des troubles médicaux dans le cadre desquels la prise d’œstrogènes est contre-indiquée ou moins souhaitable, comme dans le cas des femmes qui ont récemment connu un accouchement, qui allaitent ou qui fument et qui sont âgées de plus de 35 ans. (III-A)
- 13.
  Aucune restriction ne devrait être imposée quant à l’utilisation d’acétate de médroxyprogestérone-retard (y compris en ce qui a trait à la durée d’utilisation) chez les femmes en âge de procréer qui sont autrement admissibles à l’utilisation de ce mode de contraception. Les risques et les avantages globaux de la poursuite de l’utilisation d’acétate de médroxyprogestérone-retard devraient faire l’objet de discussions avec les utilisatrices à intervalles réguliers tout au long du traitement. (III-A)
- 14.
  Des services de counseling traitant des perturbations du cycle menstruel devraient être offerts avant la mise en œuvre d’un mode de contraception à progestatif seul. (I-A)
- 15.
  Les fournisseurs de soins devraient aviser leurs patientes des effets potentiels de l’acétate de médroxyprogestérone-retard sur la densité minérale osseuse et leur offrir des conseils en matière de « santé osseuse » (y compris en ce qui concerne la supplémentation en calcium et en vitamine D, l’abandon du tabagisme, la pratique d’exercices de port de poids et l’atténuation de la consommation d’alcool et de caféine). (III-A)
- 16.
  En présence de saignements prolongés et/ou fréquents chez des utilisatrices de contraceptifs à progestatif seul, la présence d’une grossesse, d’une infection transmissible sexuellement ou d’une pathologie génitale devrait être écartée. (III-B)
- 17.
  La possibilité d’une grossesse ectopique doit être écartée lorsqu’une grossesse en vient à se manifester chez une femme qui utilise un mode de contraception à progestatif seul. (III-A)
Canadian Contraception Consensus (Part 3 of 4): Chapter 8 - Progestin-Only Contraception
2016, Journal of Obstetrics and Gynaecology Canada
To provide guidelines for health care providers on the use of contraceptive methods to prevent pregnancy and on the promotion of healthy sexuality.
Overall efficacy of cited contraceptive methods, assessing reduction in pregnancy rate, safety, ease of use, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the relative cost and availability of cited contraceptive methods in Canada.
Published literature was retrieved through searches of Medline and The Cochrane Database from January 1994 to January 2015 using appropriate controlled vocabulary (e.g., contraception, sexuality, sexual health) and key words (e.g., contraception, family planning, hormonal contraception, emergency contraception). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from January 1994 to January 2015. Searches were updated on a regular basis in incorporated in the guideline to June 2015. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies.
The quality of the evidence in this document was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care (Table 1).
Summary Statements
- 15.
  Progestin implants have failure rates as low as permanent contraception. (II-2)
- 16.
  The use of a progestin implant immediately postpartum and post-abortion is an effective way of decreasing repeat pregnancy in adolescents and repeat abortions. (II-2)
- 17.
  The most common side effect of progestin-only contraceptive methods is menstrual cycle disturbances. (II-2) Amenorrhea is very common with depot medroxyprogesterone acetate and progestin implant use. (II-2)
- 18.
  The use of progestins given at contraceptive doses does not appear to increase the risk of venous thromboembolism, myocardial infarction, or stroke. (II-2)
- 19.
  The efficacy of progestin implants or depot medroxyprogesterone acetate is not decreased in overweight and obese women. (II-2)
- 20.
  Early weight gain with depot medroxyprogesterone acetate use is predictive of continued weight gain. (II-2)
- 21.
  Depot medroxyprogesterone acetate use is associated with a delay in resumption of ovulation. (II-2)
- 22.
  The use of depot medroxyprogesterone acetate (DMPA) is associated with a decrease in bone mineral density. This decrease is most rapid in the first 2 years of use and appears to be largely reversible once DMPA is discontinued. (I) There is no strong evidence that the use of DMPA causes osteoporosis (II-2) or increases the risk of fracture. (II-2)
- 23.
  The use of progestin-only preparations has not been shown to decrease breast milk production. (I) The small amounts of steroid hormones secreted in breast milk do not have an adverse effect on infant growth and development. (II-2)
- 24.
  Depot medroxyprogesterone acetate use is associated with a decreased risk of endometrial and ovarian cancer. (II-2)
Recommendations
- 12.
  Progestin-only methods of contraception should be considered in women with medical conditions where estrogen is contraindicated or less appropriate, such as women who are recently postpartum, breastfeeding, or in smokers over age 35. (III-A)
- 13.
  There should be no restriction on the use of depot medroxy-progesterone acetate (DMPA), including duration of use, among women of reproductive age who are otherwise eligible to use the method. The overall risks and benefits of continuing DMPA use should be discussed with DMPA users at regular intervals throughout the course of treatment. (III-A)
- 14.
  Counselling regarding menstrual cycle disturbances should be done prior to initiating a progestin-only method of contraception. (I-A)
- 15.
  Health care providers should inform patients of the potential effects of depot medroxyprogesterone acetate on bone mineral density and counsel them on “bone health,” including calcium and vitamin D supplementation, smoking cessation, weight-bearing exercise, and decreased alcohol and caffeine consumption. (III-A)
- 16.
  If prolonged and/or frequent bleeding occurs in users of progestin-only contraceptives, pregnancy, sexually transmitted infection, and genital pathology should be ruled out. (III-B)
- 17.
  Ectopic pregnancy should be ruled out if a pregnancy occurs in a woman using a progestin-only method of contraception. (III-A)
Risks of thromboembolism associated with hormonal contraceptives related to body mass index and aging in Japanese women
2016, Thrombosis Research
The aim of this study is to estimate the risk of thromboembolism related to body mass index (BMI) and aging among users of hormonal contraceptives in Japan.
A case–control study of the risk of obesity and a descriptive study of the risk of age were conducted. We used the Pharmaceuticals and Medical Devices Agency database, and extracted thromboembolic events of combined oral contraceptive (COC) products. Control data were from the National Health and Nutrition Survey in Japan. Denominator of descriptive study was from IMS Health, JPM.
A total of 306 thromboembolic events and 6423 controls were analyzed. The odds ratios (95% confidence interval) of the obesity groups (BMI ≥ 25) were 2.32 (1.71–3.15) for venous thromboembolism (VTE), 1.16 (0.62–2.18) for arterial embolism and thrombosis (ATE), and 1.83 (1.38–2.43) for overall thromboembolic events compared with the standard group (BMI of 18.5–24.9) as a reference. The estimated incidence rates of VTE, ATE and overall thromboembolic events per 10,000 person-years in users of therapeutic remedies for dysmenorrhea (35 μg ethinylestradiol combined with norethisterone, 20 μg ethinylestradiol combined with drospirenone and dienogest) among women aged 10–59 years from 2009 to 2013 were 2.38 (2.08–2.74), 0.63 (0.48–0.82), and 3.17 (2.81–3.57), respectively. This tendency was not seen for dienogest.
The risk of VTE in the obesity group among COC users was more than 2 times higher than in the standard group. The incidence rates of VTE in Japanese users of all remedies for dysmenorrhea except dienogest were as high as in people in Western countries.
Safety and Efficacy of Contraceptive Methods for Obese and Overweight Women
2015, Obstetrics and Gynecology Clinics of North America
Citation Excerpt :
The Royal College of Obstetricians and Gynaecologists United Kingdom MEC also consider combined hormonal methods to be a level 2 for women with a BMI between 30 and 34.9 kg/m2, but consider combined hormonal methods to be a level 3 for women with a BMI of 35 kg/m2 or greater.34 Nonhormonal forms of contraception, such as the copper IUD, and progestin-only methods, such as pills, DMPA, implants, and the levonorgestrel IUD, do not significantly increase the risk of VTE.35 Estrogen is prothrombotic, resulting in an increased risk of VTE with estrogen-containing methods such as the oral contraceptive pill, patch, and ring.

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Regular ArticleProgestin-only contraception and venous thromboembolism

Abstract

Introduction

Section snippets

Progestin-only hormonal contraceptives and coagulation

Progestin-only hormonal contraceptives and risk of VTE

Progestin-only hormonal contraceptives and thrombophilia

Progestin-only hormonal contraceptives and anticoagulation

Eligibility criteria for the use of hormonal contraception in women with previous VTE or thrombophilia carriers

Conclusions

Conflict of interest statement

Acknowledgements

Am J Obstet Gynecol

Am J Obstet Gynecol

Contraception

Contraception

Fertil Steril

Contraception

Maturitas

Contraception

Lancet

Lancet

Contraception

Contraception

Thromb Res

Am J Obstet Gynecol

Contraception

Contraceptive use and behavior in the 21st century: a comprehensive study across five European countries

Eur J Contracept Reprod Health Care

Clinical profile of contraceptive progestins

Eur J Contracept Reprod Health Care

Trends in the content and use of oral contraceptives in the United States 1964–88

Am J Public Health

New progestagens for contraceptive use

Hum Reprod Update

Counselling women about hormonal therapy

Thromb Res

Venous thromboembolism in women using hormonal contraceptives. Findings from the RIETE Registry

Thromb Haemost

Hormone therapy and thromboembolic disease

Curr Opin Hematol

A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways

Thromb Haemost

Emergency contraception and retinal vein thrombosis

Br J Ophthalmol

Rapid activation of haemostasis after hormonal emergency contraception

Thromb Haemost

Differential effects of progestins on hemostasis

Maturitas

Regular Article
Progestin-only contraception and venous thromboembolism