INTRODUCTION — Inherited thrombophilia is a genetic tendency to venous thrombosis (VTE), including deep vein thrombosis (DVT), pulmonary embolism, and cerebral vein thrombosis. Women with an inherited thrombophilia are at higher risk of VTE, especially during use of estrogen-progestin contraceptives and pregnancy. In making contraceptive choices, affected women need to balance the risk of VTE associated with use of various types of hormonal contraception against the risk of VTE associated with an unintended pregnancy resulting from use of less effective contraceptive methods.
This topic will discuss contraceptive counseling for females with an inherited thrombophilia. Other issues related to inherited thrombophilias are reviewed in detail separately:
●(See "Prothrombin G20210A".)
●(See "Antithrombin deficiency".)
●(See "Protein C deficiency".)
●(See "Protein S deficiency".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
GENERAL PRINCIPLES — The relative risk of venous thromboembolism (VTE) varies with the type of inherited thrombophilia (table 1). (See "Overview of the causes of venous thrombosis", section on 'Thrombotic risk in families'.)
Contraception counseling of women with an inherited thrombophilia should address the risks of both VTE and unintended pregnancy for all contraceptive methods in order to enable these women to make an informed choice. Women with an inherited thrombophilia should be counseled that pregnancy and the postpartum period are associated with a significantly increased risk of VTE, and these risks may exceed the VTE risk of a particular contraceptive method. As for all women, the general advantages and disadvantages of each contraceptive method also need to be reviewed. (See "Contraception: Counseling and selection".)
NONHORMONAL REVERSIBLE CONTRACEPTIVES — Nonhormonal reversible methods of contraception (eg, copper-releasing intrauterine contraception [IUD], male or female condom, diaphragm) have no effect on hemostasis and thus do not increase the risk of VTE in women with inherited thrombophilias .
The copper-releasing intrauterine device is an excellent option for most women because of its safety and efficacy. In contrast to condoms or the diaphragm, it does not require ongoing effort on the part of the user and is highly effective for at least 10 years after insertion (figure 1). The IUD is economical when used over as little as a two-year period and, like other nonhormonal methods, it provides prompt return of fertility after removal. The main disadvantages of the copper-releasing IUD are its initial cost and a possible increased volume of menstrual bleeding; less common issues include uterine perforation and IUD expulsion.
●Reversible nonhormonal contraceptive methods – Reversible nonhormonal contraceptive methods include:
●Permanent contraception – Discussions of permanent contraception include:
PROGESTIN-ONLY METHODS — Progestin-only methods (eg, oral, injection, intrauterine device [IUD], subdermal implant) are in the top two tiers of contraceptive efficacy (figure 1) and most available data have not demonstrated a significantly increased risk of thrombosis in users. The authors believe it is prudent to avoid injectable progestins for contraception in patients with inherited thrombophilias because (low-quality) evidence from epidemiological studies does not exclude the possibility of an increased VTE risk and alternate options are available. Additional discussion of the VTE risk associated with injectable progestin contraception is presented in related content. (See "Depot medroxyprogesterone acetate (DMPA): Efficacy, side effects, metabolic impact, and benefits", section on 'Cardiovascular and thromboembolic risk'.)
Supporting data includes:
●In a 2012 systematic review of cohort and case-control studies of women using progestin-only contraception (oral, injectable, or intrauterine but not implants) versus women in a no-progestin control group, venous thrombosis (VTE) risk was similar in both groups (adjusted relative risk [RR] 1.03, 95% CI 0.76-1.39, eight studies) . However, subgroup analysis suggested a higher risk of thrombotic events for women using an injectable progestin (RR 2.67, 95% CI 1.29-5.53, two studies), but not for those using oral progestins (RR 0.90, 95% CI 0.57-1.45, seven studies) or an intrauterine progestin (RR 0.61, 95% CI 0.24-1.53, two studies). A limitation of observational studies is the possibility that patients taking injectable progestin contraception had higher baseline risks of VTE than those using oral or intrauterine progestins. The relatively small number of thromboembolic events in women of reproductive age and the small number of studies also limit the reliability of the findings.
●In a case-control study published after the review, women with a first episode of VTE/pulmonary embolism were twice as likely to be depot medroxyprogesterone acetate (DMPA) users than were controls in the general population (odds ratio 2.2, 95% CI 1.3-4.0; 47 of 948 [5 percent] VTE cases and 23 of 902 [2.5 percent] controls were DMPA users) . In this study, use of progestin-only pills, the levonorgestrel-releasing IUD, or the progestin subdermal implant was not a significant risk factor for VTE.
For patients with an inherited thrombophilia or past history of VTE, the United States Medical Eligibility Criteria for Contraceptive Use classifies all progestin-only methods as having "advantages that generally outweigh the theoretical or proven risks" and stated that "routine screening for inherited thrombophilia is not appropriate because of the rarity of the conditions and the high cost of screening" .
Progestin-only contraceptive methods are discussed in detail separately:
●(See "Emergency contraception".)
ESTROGEN-PROGESTIN METHODS — Estrogen-progestin contraceptive methods include combined oral contraceptive pills (COCs), the transdermal patch, and the vaginal ring. Although these three methods have slightly different thrombogenic risks, they all increase the risk of venous thrombosis (VTE) and are classified as a single category by the United States Medical Eligibility Criteria for Contraceptive Use.
Our approach to estrogen-progestin contraception counseling for a woman with an inherited thrombophilia is based on her personal history of VTE, the specific thrombophilia, and her family history of VTE (see 'Individualized risk-based counseling' below). By comparison, the United States Medical Eligibility Criteria for Contraceptive Use does not provide separate recommendations based on the specific thrombophilia and describes estrogen-progestin methods as having unacceptable health risks when used by women with known thrombogenic gene variants (factor V Leiden [FVL], prothrombin G20210A, or protein S, C, or antithrombin deficiency) . Details of family history of VTE are also not considered.
Risk of venous thrombosis — Both use of estrogen-progestin contraceptives and inherited thrombophilias increase the risk of VTE above baseline (table 1). Absolute risks are difficult to determine because of the small number of these events in young women, even those with risk factors for VTE. (See "Combined estrogen-progestin contraception: Side effects and health concerns", section on 'Venous thromboembolism'.)
Baseline VTE risk — A 2007 systematic review of methodologically acceptable community and cohort studies concluded the most valid estimate of background VTE incidence in young women was 5 to 10 per 10,000 women-years, which is higher than the reference range of 0.5 to 1 per 10,000 woman-years often utilized as the baseline risk for nonuser controls in studies of VTE risk in hormonal contraception users .
VTE risk with estrogen-progestin contraceptives — Most data on VTE risk in users of estrogen-progestin contraception were derived from studies of COC users, but generally applies to other estrogen-progestin preparations. Observational studies have consistently reported a two- to sevenfold increased risk of VTE in COC users compared with nonusers [5-13], but the risk varies by dose of estrogen and may also depend on the type of estrogen and progestin [3,5,12]. The following studies show that VTE risk is 1.5- to 2-fold higher in women using third-generation COCs than in those using second-generation COCs [3,13,14]:
•A 2015 case-control study that included over 10,000 women with VTE reported a 3.64 to 4.28 increased risk of VTE in women taking COCs containing desogestrel, gestodene, cyproterone, or drospirenone compared with a 2.38 increased risk of VTE in women taking COCs with levonorgestrel .
•A 2009 national cohort study determined VTE risk for patients taking COCs with the same dose of estrogen and length of use but different progestins . Using levonorgestrel as the reference, VTE rate ratios for other progestins were: norethisterone 0.98, norgestimate 1.19, desogestrel 1.82, gestodene 1.86, drospirenone 1.64, and cyproterone 1.88. In the follow-up study, use of COCs with desogestrel, gestodene, or drospirenone were associated with at least double the risk of VTE compared with users of levonorgestrel-containing COCs .
Other studies, however, do not suggest increased risk with third-generation progestins . The estrogen implicated in these and other evaluations is ethinyl estradiol. Whether estrogens such as 17-beta estradiol or estetrol increase deep vein thrombosis (DVT) risk is not known.
VTE risk with inherited thrombophilia — The increased risk of VTE associated with COCs is even higher in users with an inherited thrombophilia, and highest in users with two or more different thrombophilic defects or homozygosity for a single defect [3,7,17,18]. In the Leiden Thrombophilia Study, the relative risks of a first VTE in normal controls, COC users, FVL carriers (heterozygotes), FVL carriers using COCs, and FVL homozygotes using COCs were approximately 1, 4, 7, 35, and 100, respectively .
For all women, the risk of VTE is substantially increased in pregnancy/postpartum, and this risk is higher than during use of estrogen-progestin contraception. The absolute, relative, and comparative risks of VTE were illustrated in a retrospective cohort study of 798 female relatives of consecutive patients (probands) with VTE and an inherited thrombophilia . Of this cohort, 301 women had FVL or the prothrombin G20210A variant (single gene defect [n = 251], combined gene defect [n = 50]) and 50 women had a first-episode VTE. Major findings were:
●The incidence of VTE in women with no, a single, or a combined thrombophilia was 0.13, 0.35, and 0.94 per 100 person-years, respectively.
●The incidence of VTE in women with no, a single, or a combined thrombophilia using estrogen-progestin contraception was 0.19, 0.49, and 0.86 per 100 pill-years, respectively.
●The incidence of VTE in women with no, a single, or a combined thrombophilia during pregnancy/postpartum was 0.73, 1.97, and 7.65 per 100 pregnancy-years, respectively.
The data show that these inherited thrombophilias are associated with a modest absolute incidence of VTE in the absence of hormonal contraception or pregnancy (table 1). The risk of VTE in estrogen-progestin contraception users is increased in women with a single or combined mutation compared with women without inherited thrombophilia (adjusted hazard ratio [HR] 2.2, 95% CI 1.1-4.0) and highly increased during pregnancy/postpartum (adjusted HR 16.0, 95% CI 8.0-32.2). It should be noted, however, that women without an inherited thrombophilia are at higher risk of VTE during pregnancy than nonpregnant women with a single thrombophilia defect who use estrogen-progestin contraception. Limitations of the study were that some VTEs were not established by objective techniques, not all relatives were tested for all thrombophilic defects, and recall bias.
For a hypothetical group of 100,000 women over one year, the authors estimated the total number of VTE events in women with a thrombophilic defect would be 586 in condom users and 556 in estrogen-progestin users without a thrombophilic defect. Estrogen-progestin users had a slightly lower rate of VTE than condom users because the latter were far more likely to have an unintended pregnancy. This model highlights the importance of accounting for contraception failure (ie, pregnancy) as well as contraception-related VTE risk when considering overall VTE risk.
Individualized risk-based counseling — The contraindications to and risks associated with use of estrogen-progestin contraceptives should be discussed with all women (see "Combined estrogen-progestin contraception: Side effects and health concerns"). Specific issues for women with a history of VTE or personal or family history of thrombophilia are reviewed below.
Personal history of venous thrombosis — We advise not starting or continuing estrogen-progestin contraceptives after a previous thrombotic episode because of the risk of recurrent VTE . This applies to both provoked and unprovoked VTE, but the risk of recurrence is higher if the episode was unprovoked.
In special circumstances (eg, women with severe, refractory dysmenorrhea, endometriosis, or pelvic pain) where no satisfactory therapeutic alternative exists, estrogen-progestin contraception can be used if anticoagulation therapy is also administered. This approach is in accordance with the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis  and United States Centers for Disease Control and Prevention, but differs from the World Health Organization 2015 guidelines which state that estrogen-containing contraception confers an unacceptable health risk during anticoagulant treatment of VTE . Support for use of hormonal contraception in women being treated for VTE comes in part from a study of over 1800 women ages <60 years (mean age 41.3 years) who were receiving either rivaroxaban or enoxaparin/vitamin K antagonist (VKA) for confirmed VTE. In this study, there were no differences in the rates of recurrent VTE among women on or off hormone therapy, women receiving estrogen-progestin or progestin-only therapy, or women receiving rivaroxaban or enoxaparin/VKA therapies . Women receiving rivaroxaban reported twice the frequency of abnormal uterine bleeding compared with women receiving enoxaparin/VKA. Anticoagulation therapy with warfarin should be closely monitored to ensure the International Normalized Ratio is in the desired range (goal range 2 to 3). Medication adherence is of critical importance if a direct oral anticoagulant is prescribed (eg, rivaroxaban) due to a relatively short half-life and lack of requirement for laboratory monitoring of coagulation.
Familial, but no personal, history of VTE — Ideally, the woman will be able to find out if her clinically affected relative(s) has a hereditary thrombophilic defect.
●If a deficiency of antithrombin, protein S, or protein C has been documented in a first-degree relative with history of VTE, we believe estrogen-progestin contraception is contraindicated if the patient also carries the defect, but is acceptable if she does not carry the defect. (See "Antithrombin deficiency" and "Protein S deficiency" and "Protein C deficiency".)
●If a single first-degree relative has a history of VTE associated with FVL or the prothrombin G20210A variant, we do not consider estrogen-progestin contraception to be absolutely contraindicated if the patient is heterozygous for the same defect and has no personal history of VTE, but we tend to discourage its use. We recommend against use of estrogen-progestin contraception in women homozygous for FVL or the prothrombin variant, or those who are double heterozygotes for FVL and the prothrombin variant. We also advise against potentially more thrombogenic methods of estrogen-progestin contraception, such as the transdermal patch and contraceptive vaginal ring. (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A" and "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)
●If multiple first-degree relatives have a history of VTE (particularly at a younger age [ie, <50 years]) but no evidence of inherited thrombophilia, they and the patient may have an as-yet-unidentified prothrombotic condition that places them at increased risk of VTE. We suggest these women avoid combined estrogen-progestin contraception. However, after appropriate counseling, women who place a higher value on the effectiveness and convenience of these contraceptives than on the uncertain risk of VTE may choose to use these drugs. We advise against potentially more thrombogenic methods of estrogen-progestin contraception, such as the transdermal patch and contraceptive vaginal ring. (See "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)
If multiple first-degree relatives have a history of VTE but have not been tested for inherited thrombophilia and patient screening detects single or multiple genetic defects, this information is helpful for balancing the risks and benefits of estrogen-progestin contraceptives and making a contraceptive choice, as described for the various thrombophilic variants in the above bullets [18,23,24].
No personal or family history of VTE, but positive testing for inherited thrombophilia — While asymptomatic carriers of inherited thrombophilias have an increased relative risk of VTE, the absolute annual risk of VTE is low for women with the two "milder" thrombophilias (heterozygous FVL or prothrombin G20210A variant) (table 2). (See "Factor V Leiden and activated protein C resistance" and "Prothrombin G20210A".)
We favor a nonhormonal or progestin-only contraceptive over COCs for women with inherited thrombophilia. However, women with a mild thrombophilia and a strong rationale for using COCs (eg, refractory pain from endometriosis) may choose to use these drugs after appropriate counseling regarding their risks and benefits . We inform women heterozygous for FVL but with no personal or family history of VTE of an estimated 0.29 percent per year increase in risk of VTE if they use estrogen-progestin contraception compared with a baseline increased risk for VTE of 0.06 percent from the thrombophilia alone . We advise against using potentially more thrombogenic methods of estrogen-progestin contraception, such as the transdermal patch and contraceptive vaginal ring. (See "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)
As women with more severe thrombophilias (antithrombin deficiency, protein C deficiency, protein S deficiency, double heterozygosity or homozygosity for FVL and/or prothrombin G20210A) have a much greater absolute risk of VTE with COC use, we strongly encourage them to use nonestrogenic contraception (table 1) . (See "Antithrombin deficiency" and "Protein C deficiency" and "Protein S deficiency" and "Contraception: Counseling and selection".)
Choice of estrogen-progestin oral contraceptive — If estrogen-progestin oral contraception is prescribed, we suggest use of a low estrogen dose (10 to 35 mcg of ethinyl estradiol) pill. Decreasing the ethinyl estradiol dose from 35 mcg to 20 or 10 mcg theoretically should be associated with fewer thromboembolic events, but this has not been proven nor has the use of (17-beta) estradiol rather than ethinyl estradiol been shown to reduce VTE risk. The degree of increased DVT risk with third-generation progestins is controversial, but we suggest use of a first- or second-generation progestin, such as norethindrone, norethindrone acetate, levonorgestrel, or ethynodiol diacetate. In women with an inherited prothrombotic defect, VTE in the first year of COC use is 10-fold greater than in subsequent years .
As discussed above, we advise against potentially more thrombogenic methods of estrogen-progestin contraception, such as the transdermal patch and contraceptive vaginal ring. (See "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)
Postpartum women — Postpartum women have an elevated risk of VTE, regardless of inherited thrombophilia status. For women with an elevated VTE risk from both pregnancy and inherited thrombophilia, postpartum contraceptive options with no or low additional risk of VTE include barrier methods, intrauterine devices (either copper or levonorgestrel), oral progestins (ie, norethindrone), and etonogestrel implants [1,3]. In general, contraceptives containing estrogen are altogether avoided for postpartum women with severe inherited thrombophilias and avoided for at least six weeks for women with mild inherited thrombophilias. Contraceptive options for postpartum and postabortion women and the risk of VTE are presented separately. (See "Contraception: Postpartum counseling and methods", section on 'Counseling regarding venous thromboembolism risk and hormonal contraception in the postpartum period'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Contraception".)
SUMMARY AND RECOMMENDATIONS
●General principles – Female patients with an inherited thrombophilia should be counseled that pregnancy and the postpartum period are associated with a significantly increased risk of venous thromboembolism (VTE). As with all patients seeking contraception, those with an inherited thrombophilia should be counseled about the advantages and disadvantages of the spectrum of contraceptive options, including the risk of unintended pregnancy.
●Inherited thrombophilia with patient history of VTE – Because this population is at increased risk of VTE, we suggest the following approaches:
•Avoid estrogen-containing contraceptives – Estrogen-progestin contraceptives are generally avoided in women with a personal history of VTE. (See 'Estrogen-progestin methods' above and "Combined estrogen-progestin contraception: Side effects and health concerns".)
•Long-acting reversible contraception – For women with an inherited thrombophilia who want to use a long-acting reversible contraceptive (LARC):
-Preference for no hormones – The copper 380 mm2 intrauterine device (IUD) is preferred choice for those who prioritize absence of hormonal side effects (including possible hemostatic effects) over a reduction in uterine bleeding. (See "Intrauterine contraception: Background and device types" and "Intrauterine contraception: Background and device types", section on 'Copper IUD'.)
-Preference for reduced menstrual bleeding – For women who want the oligomenorrhea/amenorrhea induced by progestin-only methods and are willing to accept uncertainty about a possible small increase in risk of VTE, we suggest a levonorgestrel-releasing IUD rather than the progestin-only implant because hormonal effects are primarily local (endometrium) with an IUD (Grade 2C). (See 'Nonhormonal reversible contraceptives' above and 'Progestin-only methods' above.)
•Short-acting reversible contraception – For patients with an inherited thrombophilia who want to use a short-acting reversible contraceptive, we recommend a nonhormonal contraceptive method or progestin-only method over estrogen-progestin methods (Grade 1B). Options include the copper 380 mm2 intrauterine device (IUD), internal or external condoms, diaphragms, and pericoital contraceptives. The authors prefer to avoid injectable progestins (ie, depot medroxyprogesterone acetate [DMPA]) for these patients because (low-quality) evidence from epidemiological studies does not exclude the possibility of an increased VTE risk and alternate options are available.
-(See 'Nonhormonal reversible contraceptives' above.)
-(See 'Progestin-only methods' above.)
-(See 'Individualized risk-based counseling' above.)
●Inherited thrombophilia but no VTE history – Some women with an inherited thrombophilia and no personal history of VTE may consider estrogen-progestin contraception.
•Avoid estrogen-progestin contraceptives – Because of the thrombogenic risk, we recommend avoiding estrogen-progestin contraception in the following women (Grade 1B). (See 'Individualized risk-based counseling' above.)
-Women who are homozygous for FVL or prothrombin G20210A, or those with double heterozygosity for both FVL and the prothrombin variant.
-Women who carry the same defect as a first-degree family member with VTE and deficiency of antithrombin, protein C, or protein S.
-Women who carry the same defect as a single first-degree relative with VTE and are heterozygous for FVL or prothrombin G20210A.
•Favor nonhormonal or progestin-only contraceptive – Women with multiple first-degree relatives with VTE but no evidence of inherited thrombophilia may have an as-yet-unidentified prothrombotic condition that places them at increased risk of VTE. Women with an inherited thrombophilia who have no personal or family history of VTE are at increased risk of VTE, but the absolute annual risk is low. For both of these groups of women, we favor a nonhormonal or progestin-only contraceptive. However, after appropriate counseling, women who place a higher value on the effectiveness and convenience of estrogen-progestin contraceptives than on the uncertain risk of VTE may choose to use these drugs. (See 'Familial, but no personal, history of VTE' above and 'No personal or family history of VTE, but positive testing for inherited thrombophilia' above.)
•Potential use of estrogen-progestin contraception – If patients with multiple affected first-degree relatives or those with an inherited thrombophilia but no history of VTE choose to use estrogen-progestin oral contraception, we prescribe a low estrogen dose (10 to 35 mcg of ethinyl estradiol) pill. Decreasing the ethinyl estradiol from 35 mcg to 20 or 10 mcg theoretically should be associated with fewer thromboembolic events, but this has not been proven. We also suggest norethindrone, norethindrone acetate, levonorgestrel, or ethynodiol diacetate for the progestin component. (See 'Choice of estrogen-progestin oral contraceptive' above.)
We advise against use of potentially more thrombogenic methods of estrogen-progestin contraception, such as the transdermal patch and contraceptive vaginal ring. (See "Contraception: Transdermal contraceptive patches" and "Contraception: Hormonal contraceptive vaginal rings".)
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