Letter to the EditorORTHO EVRA® and venous thromboembolism: an update☆
References (2)
- JickS.S. et al.
Risk of nonfatal venous thromboembolism in women using a contraceptive transdermal patch and oral contraceptives containing norgestimate and 35 μg of ethinyl estradiol
Contraception
(2006) - JickS.S. et al.
Further results on the risk of nonfatal venous thromboembolism in users of the contraceptive transdermal patch compared to users of oral contraceptives containing norgestimate and 35 μg of ethinyl estradiol
Contraception
(2007)
Cited by (30)
An overview of contraception in women with obesity
2023, Best Practice and Research: Clinical Obstetrics and GynaecologyThe use of safe and effective contraception is essential for preventing unplanned pregnancy in women of all body sizes. When counseling women with obesity about contraception, it is important to consider the pharmacokinetic alterations of obesity on various modern contraceptive methods. However, evidence is reassuring that most contraceptive methods are safe and effective in women with obesity. Individual countries and the World Health Organization have published Medical Eligibility Criteria to guide contraceptive selection in women with medical issues including obesity. When choosing contraception, specific risks of the method relative to any underlying medical disorders must also be balanced against the risks of unintended pregnancy in this group.
Hormonal therapies and venous thrombosis: Considerations for prevention and management
2022, Research and Practice in Thrombosis and HaemostasisVenous thromboses are well‐established complications of hormonal therapy. Thrombosis risk is seen with both hormonal contraceptive agents and with hormone replacement therapy for menopause and gender transition. Over the past several decades, large epidemiological studies have helped better define these risks.
To review and discuss the differences in thrombosis risk of the many of hormonal preparations available as well as their interaction with patient‐specific factors.
We conducted a narrative review of the available literature regarding venous thrombosis and hormonal therapies including for contraception, menopausal symptoms, and gender transition.
Thrombosis risk with estrogen‐containing compounds increases with increasing systemic dose of estrogen. While progesterone‐only–containing products are not associated with thrombosis, when paired with estrogen in combined oral contraceptives, the formulation of progesterone does impact the risk. These components, along with patient‐specific factors, may influence the choice of hormonal preparation. For patients who develop thrombosis on hormonal treatment, anticoagulation is protective against future thrombosis. Duration of anticoagulation is dependent on ongoing and future hormone therapy choice. Finally, the optimal management of hormone therapy for individuals diagnosed with prothrombotic illnesses such as COVID‐19 remains unclear.
When contemplating hormonal contraception or hormone replacement therapy, clinicians must consider a variety of factors including hormone type, dose, route, personal and family history of thrombosis, and other prothrombotic risk factors to make informed, personalized decisions regarding the risk of venous thrombosis.
Genetic variation in the first-pass metabolism of ethinylestradiol, sex hormone binding globulin levels and venous thrombosis risk
2017, European Journal of Internal MedicineUse of ethinylestradiol, one of the active ingredients in combined oral contraceptives, affects the incidence of venous thrombosis. To explain why some women develop thrombosis when using oral contraceptives and others do not, we hypothesized a role for the first-pass metabolism of ethinylestradiol in the liver. We set out to determine the association between genetic variation in the first-pass metabolism of ethinylestradiol, venous thrombosis risk and the effect on Sex-hormone-binding-globulin (SHBG) levels.
Premenopausal women were included from two case-control studies: LETS (103 cases; 159 controls) and MEGA (397 cases; 796 controls). Haplotype-tagging SNPs were selected in 11 candidate genes; COMT, CYP1A2, CYP2C9, CYP3A4, CYP3A5, SULT1A1, SULT1E1, UGT1A1, UGT1A3, UGT1A9, UGT2B7. Venous thrombosis risk was expressed as odds ratios (OR) with 95% confidence intervals (CI). For SHBG levels, mean differences with 95%CI were estimated in combined oral contraceptive-using control subjects from the MEGA study.
Two copies of haplotype D in the UGT2B7 gene increased venous thrombosis risk (ORLETS: 3.78; ORMEGA: 2.61) as well as SHBG levels (mean difference 27.6 nmol/L, 95%CI: − 61.7 to 116.9 compared with no copies) in oral contraceptive users and not in non-users. In oral contraceptive users, haplotype A and B in the CYP3A4 gene were associated with venous thrombosis risk, but not in non-users; however, the effect on SHBG levels was not directional with the risk. None of the other haplotypes were associated with venous thrombosis.
Genetic variation in the UGT2B7 gene may, in part, explain venous thrombosis risk in combined oral contraceptive users.
No. 329-Canadian Contraception Consensus Part 4 of 4 Chapter 9: Combined Hormonal Contraception
2017, Journal of Obstetrics and Gynaecology CanadaTo 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, and side effects; the effect of cited contraceptive methods on sexual health and general well-being; and the availability of cited contraceptive methods in Canada.
Medline and the Cochrane Database were searched for articles in English on subjects related to contraception, sexuality, and sexual health from January 1994 to December 2015 in order to update the Canadian Contraception Consensus published February-April 2004. Relevant Canadian government publications and position papers from appropriate health and family planning organizations were also reviewed.
The quality of the evidence is rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice are ranked according to the method described in this report.
- 1.
Although highly effective with perfect use, typical use failure rates for combined hormonal contraceptives, including the combined oral contraceptive pill, are as high as 9% (II-2).
- 2.
The majority of qualified studies do not indicate decreased combined oral contraceptive pill efficacy in obese women; however, a small increase in contraceptive failure in women with a body mass index greater than 30 cannot be excluded (II-2).
- 3.
Combined oral contraceptive pills are associated with a number of non-contraceptive benefits, including but not limited to decreased menstrual bleeding, decreased acne, fewer endometriosis-related symptoms, and a decreased risk of ovarian and endometrial cancers (II-2).
- 4.
Combined oral contraceptive pills (COCs) are associated with an increased risk of venous thromboembolism (II-2). Potential differences in the risk of venous thromboembolism attributable to different progestin types and estrogen dosing in low-dose COCs do not currently justify preferential prescribing (III).
- 5.
Low-dose combined oral contraceptive pills (containing less than 50 μg of ethinyl estradiol) are not associated with an increased risk of myocardial infarction or cerebrovascular accident in women with no additional risk factors (II-2).
- 6.
Current epidemiological studies suggest that there is no increase in the risk of breast cancer or breast cancer mortality in women who have used combined oral contraceptive pills (COCs) compared with non-users (II-2). There may be a slight increase in breast cancer in current and/or recent COC users (II-2). The use of COCs in BRCA1/2 carriers is controversial but appears to be associated with a decreased risk of ovarian cancer and no increase in the risk of breast cancer (II-2).
- 7.
Combined oral contraceptive pills (COCs) are associated with a decreased risk of ovarian, endometrial, and colorectal cancers (II-2). A possible association has been shown between COC use and risk of cervical cancer (II-2), but causation has not been demonstrated.
- 8.
A blood pressure measurement is the only examination and/or investigation that is required prior to initiating combined hormonal contraception (CHC) in women who are otherwise healthy by history (II-2). Baseline weight and body mass index assessment might be helpful for monitoring changes in CHC users. Pelvic examination, Pap test, screening for sexually transmitted infections, and thrombophilia screening are not required prior to initiating CHC (III).
- 9.
Combined oral contraceptive pills and other combined hormonal contraception (CHC) can be started at any time during the menstrual cycle provided that pregnancy or the possibility of pregnancy can be reasonably ruled out. Where there is uncertainty, the benefits of starting CHC likely outweigh any risks (III).
- 10.
Starting combined hormonal contraception immediately (Quick Start) may improve short-term compliance and is not associated with an increase in unscheduled bleeding or other side effects (I).
- 11.
The highest risk of ovulation occurs when the hormone-free interval is prolonged for more than 7 days, either by delaying the start of combined hormonal contraception (CHC) or by missing active hormone doses during the first or third weeks of CHC (I). Ovulation rarely occurs after 7 consecutive days of CHC use (II-2).
- 12.
Emergency contraception (EC) and back-up contraception may be required in some instances of missed combined hormonal contraception (CHC), particularly when the hormone-free interval has exceeded 7 days. EC is rarely indicated for missed CHC in the second or third week of the cycle unless there are repeated omissions or failure to use back-up contraception after the missed doses (III).
- 13.
Combined oral contraceptive pill exposure just prior to or during pregnancy is not associated with an increased risk of major birth defects (II-2).
- 14.
The effectiveness of combined hormonal contraception (CHC), including combined oral contraceptive pills, may be affected by other medications, including but not limited to some anticonvulsants, some antiretrovirals, rifampicin, and griseofulvin. CHCs may affect the serum levels of other medications, including some anticonvulsants and antiretrovirals (II-2).
- 15.
The contraceptive patch may be less effective in women with a body weight ≥90 kg (II-2).
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Compared with the combined oral contraceptive pill, transdermal contraceptive patch use is associated with less breakthrough bleeding and spotting but more breast discomfort or pain, nausea and vomiting, and dysmenorrhea (I).
- 17.
Pharmacokinetic studies indicate that serum hormone concentrations of ethinyl estradiol and norelgestromin are maintained at ovulation inhibitory levels throughout at least 9 days of continuous transdermal contraceptive patch wear (II-2).
- 18.
The vaginal contraceptive ring is associated with less unscheduled bleeding than the combined oral contraceptive pill and the duration of menstrual bleeding is significantly shorter than that seen with the contraceptive patch (I).
- 19.
Serum levels of ethinyl estradiol and etonorgestrel are maintained at ovulation inhibitory levels for at least 28 days after the vaginal contraceptive ring has been inserted (II-2).
- 20.
Continuous and/or extended regimens of combined hormonal contraception (CHCs) have similar rates of adherence and effectiveness compared with 28-day cyclic CHC regimens (I).
- 21.
Continuous and/or extended (C/E) regimens of combined hormonal contraception (CHC) are associated with significantly less menstruation-associated symptoms than are cyclic CHC (I). Bleeding and/or spotting with C/E CHC regimens decreases with each successive cycle and is similar to or less than that with cyclic CHC (I).
- 1.
Health care providers should give clear instructions for hormonal contraceptive use, including how to manage missed hormonal contraception, as part of contraceptive counselling. Women should be provided with resources to refer to in the event of missed and/or delayed hormonal contraceptives or if they develop any signs of a serious adverse event while using hormonal contraception (III-A).
- 2.
Health care providers should consider advising women who are initiating contraception to start their combined hormonal contraception (CHC) immediately (Quick Start) provided that they are reasonably certain that the woman is not pregnant. Back-up contraception (barrier method) or abstinence should be used for the first 7 consecutive days of CHC use unless CHC was initiated on the first day of menses (I-A).
- 3.
Health care providers should consider the possibility of irregular pill taking, concomitant medication use, malabsorption, uterine or cervical pathology, pregnancy, or chlamydial infection in women presenting with persistent unscheduled bleeding on the combined oral contraceptive pill (III-A).
- 4.
If 1 combined oral contraceptive pill or other combined hormonal contraception (CHC) method is missed in the first week of use, back-up contraception or abstinence should be used until the CHC method has been used for 7 consecutive days. In the case of missed CHC in the second or third week of hormones, the hormone-free interval should be eliminated for that cycle (III-A).
- 5.
Back-up contraception should be used when 3 or more consecutive doses/days of combined hormonal contraception (CHC) have been missed in the second or third week of hormone use until the CHC has been used for 7 consecutive days. For practical reasons, the scheduled hormone-free interval should be eliminated in these cycles (I-A).
- 6.
Health care providers should be aware of other medications being used by combined hormonal contraception users and the possibility of drug interactions that could affect serum levels and effectiveness of either medication (II-2A).
- 7.
Health care professionals should be aware of the option of using continuous and/or extended combined hormonal contraception regimens and consider offering them to women for contraception, medical reasons, and personal preferences (III-A).
- 8.
Women using continuous and/or extended combined hormonal contraception regimens should be counselled about expected bleeding patterns and how to manage unscheduled bleeding or spotting (III-A).
- 9.
When a specific product has been prescribed to a woman, she should be informed if a generic substitution is being considered and her health care provider should be advised if a substitution is made. The woman should have the option to agree or disagree to the substitution and be informed about any difference in cost for a specific product (III-B).
- 1.
Stroke and Etonogestrel/Ethinyl Estradiol Ring (NuvaRing): Clinical, Radiological, and Prognostic Features
2017, Journal of Stroke and Cerebrovascular DiseasesA recent study found that NuvaRing (a vaginal contraceptive ring containing 15 µg ethinyl estradiol and 120 µg etonogestrel) has 2.5 times increased relative risk of thrombotic stroke compared to nonuse.
We studied a case series of 19 such patients as well as prior published case reports to clarify clinical, radiological, and prognostic features.
Medical records and imaging for 18 cases were initially systematically reviewed for consultation in a class action lawsuit. One case was seen personally outside of litigation. All 19 cases were entered into a database detailing clinical, radiological, and prognostic features as well as other potential risk factors. A literature search identified 8 additional cases.
Average age at stroke was 31.7 ± 9.8 years; average duration of NuvaRing use prior to stroke was 11.2 months. Arterial stroke occurred in 10 of 19 (52%); 1 of 10 (10%) was hemorrhagic. Venous sinus thrombosis was present in 11 of 19 (58%) on initial imaging; 6 of 11 (54%) were hemorrhagic. The most common presenting symptom was headache (7 of 19 [37%]) and motor weakness (7 of 19 [37%]). A hypercoagulable condition was present in 3 of 19 (16%); 3 of 19 (16%) had history of hypercoagulable disease in a first-degree relative. Mortality was .5%; 8 of 19 (42%) fully recovered and 3 of 19 (15%) were discharged to rehabilitation.
In this largest case series of NuvaRing-associated stroke to date, approximately half of the strokes are venous and half are arterial. Stroke typically occurred within the first year of use, and as soon as 2 weeks after NuvaRing initiation.
Nonoral combined hormonal contraceptives and thromboembolism: a systematic review
2017, ContraceptionCitation Excerpt :We did not identify any studies examining combined injectable contraceptives. There were six articles that described venous events among patch users compared with COC users (Fig. 1) [12,14–16,18,19]. Two were cohort studies [18,19], and the remaining were case–control studies.
Combined hormonal contraceptives (CHCs), containing estrogen and progestin, are associated with an increased risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) compared with nonuse. Few studies have examined whether nonoral formulations (including the combined hormonal patch, combined vaginal ring and combined injectable contraceptives) increase the risk of thrombosis compared with combined oral contraceptives (COCs).
The objectives were to examine the risk of VTE and ATE among women using nonoral CHCs compared to women using COCs.
We searched the PubMed database for all English language articles published from database inception through May 2016. We included primary research studies that examined women using the patch, ring or combined injectables compared with women using levonorgestrel-containing or norgestimate-containing COCs. Outcomes of interest included VTE (deep venous thrombosis or pulmonary embolism) or ATE (acute myocardial infarction or ischemic stroke). We assessed the quality of each individual piece of evidence using the system developed by the United States Preventive Services Task Force.
Eight studies were identified that met inclusion criteria. Of seven analyses from six studies examining VTE among patch users compared with levonorgestrel- or norgestimate-containing COC users, two found a statistically significantly elevated risk among patch users (risk estimates 2.2–2.3), one found an elevated risk that did not meet statistical significance (risk estimate 2.0), and four found no increased risk. Of three studies examining VTE among ring users compared with levonorgestrel COC users, one found a statistically significantly elevated risk among patch users (risk estimate 1.9) and two did not. Two studies did not find an increased risk for ATE among women using the patch compared with norgestimate COCs. We did not identify any studies examining combined injectable contraceptives.
Limited Level II-2 good to fair evidence demonstrated conflicting results on whether women using the patch or the ring have a higher risk of VTE than women using COCs. Evidence did not demonstrate an increased risk of ATE among women using the patch. Overall, any potential elevated risk likely represents a small number of events on a population level. Additional studies with standard methodology are needed to further clarify any associations and better understand mechanisms of hormone-induced thrombosis among users of nonoral combined hormonal contraception.
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This study was funded by a grant from Johnson and Johnson Pharmaceutical Research and Development.