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Contraception-Related Venous Thromboembolism in Adolescents Sarah H. O’Brien, MD, MSc1,2 1 Division of Pediatric Hematology/Oncology, Nationwide Children’s

Hospital, The Ohio State University, Columbus, Ohio 2 Center for Innovation in Pediatric Practice, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio

Address for correspondence Sarah H. O’Brien, MD, MSc, Nationwide Children’s Hospital, 700 Children’s Drive, Room ED553, Columbus, OH 43205 (e-mail: [email protected]).

Abstract

Keywords

► deep vein thrombosis ► pulmonary embolism ► inherited thrombophilia ► adolescents

Venous thromboembolism (VTE) is a rare but serious complication of combined hormonal contraception. While the absolute risk of VTE is low in adolescents, thrombotic events in contraception users younger than the age of 20 years account for 5 to 10% of total contraception-related VTE events in population studies, because of the high frequency of contraception use in adolescents. An increased risk of VTE exists not only with oral contraceptives, but also the contraceptive patch and vaginal ring. Most adolescents who experience contraception-related VTE have additional transient or inherited thrombotic risk factors at the time of VTE. Although the presence of inherited thrombophilia impacts the risk of contraception-related VTE, thrombophilia screening before contraception prescribing should be targeted only to high-risk populations. Pediatric institutions, caregivers, and young women need to be aware of the risk of VTE with estrogen-containing contraception, and maintain a high index of suspicion for this complication in women using these agents.

Venous thromboembolism (VTE) is a rare but serious complication of combined hormonal contraception (CHC) use. The estrogen component of these agents is known to be primarily responsible for this increased risk, and the mechanism is an estrogen-induced resistance to protein C.1 Because of the relatively lower risk of VTE in younger patients, the epidemiology of contraception-related VTE, and risk factors for this complication, have not been well studied. However, because of the potential morbidity caused by VTE, efforts to better understand and prevent this complication are needed. Women who experience a contraception-related VTE remain at increased risk for a subsequent VTE and are also at risk for postthrombotic syndrome, a chronic condition that can include extremity pain, swelling, varicose veins, and even skin ulcerations in its most severe manifestations.

Venous Thromboembolism and Combined Oral Contraceptives Hundreds of millions of women worldwide use hormonal contraception at some point during their reproductive years.

published online December 19, 2013

Issue Theme Hot Topics V; Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).

The majority of studies regarding contraception and VTE have focused on combined oral contraceptives (COC), the most commonly used hormonal contraception. CHC is a broader term that applies to any agent containing estrogen and progestin, and includes oral, transdermal, and vaginal routes of delivery. Although adolescents are not typically considered a population at high-risk for VTE, recognition of this complication is important, as adolescents are the primary seekers of hormonal contraception, particularly COC, in many areas of the world. In addition to providing effective contraception, these agents play a role in the management of several other common conditions in adolescents, including heavy menstrual bleeding, menstrual cycle irregularity, dysmenorrhea, premenstrual syndrome, ovarian cysts, endometriosis, hyperandrogenism, and acne. Hormonal contraception containing both estrogen and progestin, or CHC, has been associated with deep vein thrombosis and pulmonary embolism in young women. There are even case reports of pulmonary venoocclusive disease, a rare cause of pulmonary hypertension, in two young women (14 and 18 years) shortly after initiating COC.2 Fortunately, while

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Semin Thromb Hemost 2014;40:66–71.

arterial thrombotic events have also been associated with the use of hormonal contraception, there does not appear to be an increased risk of myocardial infarction or ischemic stroke with COC use in healthy, nonsmoking women younger than 35 years.3 Age is a known risk factor for the development of VTE, and therefore not surprisingly, adolescent females have the lowest absolute risk of COC-related VTE when compared with older COC users (►Table 1), and the absolute risk of contraceptionrelated VTE in young women is consistently less than 1 per 1,000 exposure years in published studies. However, given the large numbers of adolescents using these agents, VTE events in users younger than 20 years still accounted for 5.9 to 9.6% of total events in the largest population studies of contraception-related VTE.4–7 These same large cohort studies also clearly demonstrate that despite the low-absolute risk, the use of COC does lead to a significant increase in the relative risk of VTE among adolescent females. In a large Danish cohort study (2001–2009), the incidence of VTE in women aged 15 to 19 years currently using COC was 4.2 events per 10,000 exposure years, as compared with 0.7 events per 10,000 years in nonusers.6 These investigators have also examined the risk of VTE with all types of hormonal contraception by linking four patient registries in Denmark.4 In this very large study of 10.4 million woman-years during the time period 1995 to 2005, the adolescent age group (15–19 years) accounted for 13% of women-years (1,359,821 total woman-years) and 5.9% (250/ 4,213) of VTE events. Consistent with other studies, the adjusted rate ratio was lowest in adolescents and was 0.39 (0.33–0.45) when compared with the reference group of 30- to 34-year-old women. Although this hallmark study did not separately analyze the adolescent age group, it did confirm several key findings in contraception-related VTE research that are worth reviewing. First, the risk of VTE in current users of COC decreases with duration of use and decreasing estrogen dose. Second, COC containing the progestin formulations of desogestrel, gestodene, or drospirenone are associated with a significantly higher risk of VTE than COC with levonorgestrel. And finally, progestin only pills and progestin-releasing

O’Brien

intrauterine devices (IUDs) were not associated with an increased risk of VTE. A few features unique to adolescents should be considered when examining the epidemiology of contraception-related VTE. First, it is quite possible that low suspicion of VTE in otherwise healthy young women presenting with symptoms such as chest pain, shortness of breath, or leg pain, leads to underdiagnosis of these complications. In fact, the estimated population risk in the literature for adolescent women often seems low from the point of view of the practicing hematologists caring for these women.8 Adolescents are also more likely to be new users of a hormonal contraceptive, and the risk of contraception-related VTE is known to be highest in the first 6 to 12 months of use, particularly in first-time users.9 Finally, younger women are more likely to use newer oral contraceptives than older women.4 This is an important point, as VTE is a rare and delayed adverse event, and therefore the thrombotic risks of new contraceptive agents are not fully known at the time these products are introduced into the market. Both “third generation” COC (desogestrel and gestodene containing products) and drospirenone-containing products were widely prescribed to adolescent females upon their initial release.

Contraceptive Patch and Other Nonoral Contraceptives Because of the widely known association between birth control pills and blood clots, there can sometimes be misunderstandings in the medical and lay community that nonoral formulations are somehow safer with regard to the risk of blood clots. Therefore, it is important to have an understanding of the literature to best counsel young women making contraceptive decisions. Unfortunately, as with oral agents, large studies of adolescents, or even subanalyses of the adolescent population in large population studies, are not available. When transdermal contraception was approved in the early 2000s (2001 in the United States and 2002 in Europe), these agents seemed particularly appealing for adolescents. Women using these products could change a birth control

Table 1 Incidence of venous thromboembolism and adjusted rate ratios according to age in current users of combined oral contraceptives and nonusers6 Age (y), range

Nonusers

Current users

Incidence per 10,000, exposure years

Incidence per 10,000, exposure years

Adjusted rate ratio (95% CI)

p

15–19

0.7

4.2

1 (reference)



20–24

2.1

4.8

1.32 (1.13–1.54)

< 0.001

25–29

2.9

6.8

1.99 (1.66–2.38)

< 0.001

30–34

3.2

8.7

2.91 (2.40–3.55)

< 0.001

35–39

3.5

12.1

4.01 (3.31–4.87)

< 0.001

40–44

4.8

15.2

5.29 (4.36–6.41)

< 0.001

45–49

5.8

20.8

6.58 (5.43–7.99)

< 0.001

Abbreviation: CI, confidence interval. Seminars in Thrombosis & Hemostasis

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Contraception and VTE in Adolescents

Contraception and VTE in Adolescents

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patch once a week, rather than having to take an oral medication daily. However, pharmacokinetic studies subsequently demonstrated 60% higher plasma levels of estrogen in women using transdermal patches as compared with those using COC-containing standard doses of estrogen.10 Despite higher mean circulatory levels of estrogen among users of the patch, clinical studies have not confirmed that these findings translate into an increased risk of VTE events as compared with COC users. An early study utilized PharMetrics data (a United States– based administrative health care claims data source) to compare the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using COCs containing norgestimate and 35 µg of estrogen.11 Approximately 40% of the 68 cases in this cohort were women aged 15 to 29 years. The overall incidence rate for VTE was 5.3 per 10,000 women-years among users of the contraceptive patch, as compared with 4.2 per 10,000 women-years among COC users. The age-adjusted incidence rate ratio for current use of the patch versus COC was 1.1 (95% CI, 0.7–1.8), therefore demonstrating that the risk of VTE was similar between the two agents. Since that time, several studies have examined the rate ratio of VTE in women using the transdermal patch as compared with those using a COC with norgestimate. Incidence rate ratios have ranged from 1.1 to 2.4, with four of seven studies demonstrating a statistically significant increase in VTE risk with the patch.5 Whether the patch has a higher risk for VTE than COC may never be decided, but it is certainly not a safer option, and the potential risks should be considered carefully when prescribing to an adolescent with other thrombotic risk factors (obesity, tobacco use, etc.). When assessing thrombotic risk, it is also important to consider the use of electronic cigarettes (e-cigarettes), as these products are being increasingly used by adolescents and the cardiovascular and thrombosis risks remain unknown.12 There can also be a misconception that transvaginal use of estrogen is a local form of contraception and therefore could not lead to an increased risk of VTE. However, vaginal rings do in fact lead to activation of the hemostatic system.13 In a national cohort in Denmark (2001–2010), 39 confirmed VTE events were observed with the combined contraceptive vaginal ring, corresponding to an incidence of 7.8 events per 10,000 women-years of use and an adjusted relative risk of 6.5 (range, 4.7–8.9) compared with nonusers of hormonal contraception.5

Low Dose Estrogen Combined Oral Contraceptives While a standard estrogen dose for a COC is 30 to 35 µg, many of the newer agents on the birth control market are oral contraceptives with very low doses of estrogen (20 µg or even less). The rationale for lower estrogen concentrations in COC preparations is an attempt to reduce the risk of adverse events, primarily thrombotic events. Once again, however, considering the risk/benefit ratio for an adolescent user may be a more complex process. Estrogen is required for normal pubertal skeletal growth and maturity in adolescent females. A review of the literature Seminars in Thrombosis & Hemostasis

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by Agostino and Di Meglio demonstrate consistent evidence that COCs with 30 µg of ethinylestradiol are adequate to ensure sufficient bone accrual during adolescence.14 This review also reveals, however, that studies of 20 µg COCs cast doubt on the ability of these agents to support peak bone mass acquisition. As well, studies in the general female population have not demonstrated that the incidence of thrombosis is in fact lower in users of 20 µg as compared with 30 to 35 µg COCs. Recently, COCs with estradiol or estradiolvalerate in lieu of the traditional ethinylestradiol have been introduced.15 These COCs show a lower hepatic estrogenicity with weaker effects on thrombogenic markers than ethinylestradiol-containing COCs. However, the VTE incidence with estradiol-COCs, or how this risk compares to traditional COCs, is unknown at present.

Additional Risk Factors for ContraceptionRelated Venous Thromboembolism Although it is true that the mode of delivery, estrogen dose, and progestin type can all influence the risk of contraceptionrelated VTE, women who experience this complication are likely to have additional acquired or inherited thrombotic risk factors. In a study of 400 Czech women with VTE while on oral contraceptives, VTE solely attributed to COC occurred in 57% of women, whereas an additional transient (acquired) risk factor was recognized in the other 43% of cases.16 The most common transient risk factors included administration of plaster cast (n ¼ 55), surgery (n ¼ 31), calf injury (n ¼ 28), immobilization (n ¼ 22), arthroscopy (n ¼ 15), long distance travel (n ¼ 14), and strenuous sports activity (n ¼ 8). There are many chronic medical conditions that can also predispose women to developing thrombosis, particularly during times of active disease or acute exacerbations. It is important to consider that the majority of population studies of VTE and contraception exclude women with conditions such as cancer, inflammatory disease, autoimmune disease, or renal failure. Investigators choose to exclude these patients to avoid confounding because of preferential prescribing. However, this approach means that we do not have an understanding of the true risk of contraception-related VTE in medically complicated young women. Modest associations between smoking and VTE have been identified as well as the increased risk of VTE among women with a diagnosis of obesity, or a positive family history of thrombosis. Unfortunately, it is notoriously difficult to identify these thrombotic risk factors in administrative data sources, the most common data source used in population studies of contraception-related VTE. In a community-based, case-control German study, medical data were abstracted from patient charts and data on personal characteristics were collected via self-administered questionnaires.17 In this study, obesity, family history of VTE, and personal history of VTE were in fact more prevalent among cases than controls. Although adolescent-specific studies on this topic are few and far between, there are two published single-institution reports that confirm the importance of additional VTE risk

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O’Brien

Fig. 1 Additional risk factors for venous thromboembolism (VTE) in adolescents with hormonal contraception-related VTE (n ¼ 38). Results combined from two single institution studies.18,19 Family history was only routinely captured in one study, 18 and factor VIII was only routinely captured in one study.19

factors in the development of contraception-related VTE. Our own institution performed a retrospective study of 26 young women (range, 12–21 years) with contraception-related VTE.18 The vast majority (96%) of patients had at least one VTE risk factor in addition to COCs, and 42% had two or more additional risk factors. The most common additional risk factor was obesity. Our results were similar to those published for a small cohort in the Czech Republic (►Fig. 1).19 In the Czech study, all patients were routinely tested for a variety of inherited and acquired laboratory risk factors, and factor VIII elevation was commonly identified. Several studies have identified elevated FVIII (greater than 150%) as an independent risk factor for venous and arterial thrombosis,20–22 and it is being added to an increasing number of screening laboratory panels for inherited thrombophilia. However, it has not been well studied with respect to hormonal contraception in particular, and additional studies are needed.

Inherited Thrombophilia and ContraceptionRelated Venous Thromboembolism In addition to transient and chronic-acquired medical conditions, inherited thrombophilias are also known to impact the relative risk of contraception-related VTE. In a study of 400 women with COC-related VTE, a systematic laboratory evaluation for inherited thrombophilia was performed in all the patients.16 In this cohort, the frequency of thrombophilia was as follows: heterozygous factor V Leiden (FVL) 35%, heterozygous prothrombin-20210A 5%, antithrombin deficiency 1.8%, protein S deficiency 1%, and protein C deficiency 0.8%. The frequency of inherited thrombophilia in women with VTE solely due to COC was significantly higher as compared with women with VTE associated with COC plus additional risk factors (33.5 vs. 15.25%, p < 0.0001). Of interest, the incidence of thrombophilia was not significantly different in women younger or older than 26 years at the time of their presentation with VTE (p ¼ 0.313).

As it is by far the most common inherited thrombophilia, FVL is also the most studied thrombophilia with respect to contraception-related VTE. When compared with the risk of VTE in non-COC users without FVL, the risk of VTE is increased by a factor of 35 in women who both carry the mutation and use COC.3 The absolute risk in otherwise healthy women, however, is still quite low. In a prospective cohort study of 470 asymptomatic carriers of the FVL mutation, the annual incidence of VTE was 1.8% per year of COC use.23 Routine laboratory screening for inherited thrombophilia before initiation of combined hormonal contraceptives is not recommended and has not been determined to be cost effective.24,25 In one such analysis, over 92,000 FVL carriers would need to be identified and stopped from using COCs to prevent one VTE-related death, at a cost of more than $300 million.25 As well, because of the commonality of FVL alone, universal thrombophilia screening would deny 5% of white women the contraceptive and noncontraceptive benefits of COCs. Although cost-effective analyses have not been performed specifically for the adolescent population, one can imagine that the number needed to screen to prevent one VTE or one death would be substantially higher in adolescents given their lower absolute risk of developing VTE. Thrombophilia testing should be performed before prescribing hormonal contraception in adolescents with a compelling family history of VTE. When taking a family history, it is helpful to note whether VTE occurred in first-degree relatives younger than 45 years and/or first-degree relatives without apparent-acquired risk factors.3,8 Clinicians should identify if there are family members with multiple miscarriages, stillbirths, or premature births. Thrombophilia testing may also inform risk/benefit discussions in adolescents with multiple risk factors for VTE such as obesity (an increasing epidemic in pediatrics), cigarette smoking, or chronic diseases such as diabetes. What is the best approach to prescribing contraception for adolescents with a personal history of thrombosis or thrombophilia? Progestin-only methods are the first line in these Seminars in Thrombosis & Hemostasis

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Contraception and VTE in Adolescents

Contraception and VTE in Adolescents

O’Brien

young women, as in general these agents have not been demonstrated to increase the risk of VTE.26 There are several progestin-only options available, including oral progestin pills and depot medroxyprogesterone acetate (DMPA, an injectable administered every 3 months). Long-acting progestin-only options include etonogestrel subcutaneous implants, and the levonorgestrel IUD. In one of the large Danish cohort studies, neither progestin-only pills nor hormone-releasing IUDs conferred any increased risk of VTE when compared with nonusers of hormonal contraception.4 One recent study that has received a lot of attention in the field suggested an increased risk of VTE in users of DMPA compared with nonusers of hormonal contraception.27 However, in this cohort of 1,592 patients, only 20 patients were DMPA users. Additional and larger studies are needed, particularly as DMPA is an attractive option for adolescents who have difficulty with daily medication compliance. Although several options are available, progestin-only agents do have drawbacks, such as an increased chance of breakthrough bleeding (the most common reason for discontinuation), the need for subcutaneous injections, or the need to undergo a minor procedure to place long acting progestin-only agents. Although current recommendations from the World Health Organization state that COC use represents an unacceptable health risk for women with any thrombogenic mutation, these recommendations are controversial when it comes to mild thrombophilias such as FVL and prothrombin-20210A.28 Whenever counseling a patient and family on the risks and benefits of COC, especially in those who have tried and failed progestin-only methods, it is always important to remember that the risk of VTE during pregnancy and the postpartum period is substantially higher than the risk VTE with COC. In one large cohort of women with a positive family history of VTE, COC use, and pregnancy were independent risk factors for VTE, with the highest risk during pregnancy postpartum, as evidenced by an adjusted hazard ratio of 16.0 (range, 8.0–32.2), as opposed to 2.2 (range, 1.1–4.0) during COC use.22 These authors, and other experts, have advocated for reconsideration of the policy to contraindicate COC use in asymptomatic women with mild inherited thrombophilias, especially for those patients in whom FVL was discovered incidentally (no personal or compelling family history of thrombosis). Rather, detailed counseling should be performed on a case-by-case basis.

days to weeks before the more obvious symptoms of leg pain, extremity swelling, and discoloration occur. In a retrospective analysis of 86 women, ages 15 to 25 years undergoing ventilation/perfusion scintigraphy because of suspicion of pulmonary embolism, PE was detected in only 3 (10%) of the 29 patients not using COC, but in 42% of the 57 women using COC.29 The risk of VTE should also be considered in hospitalized and postsurgical adolescents using any type of CHC, and pediatric facilities may be less aware of these risks. In women using COC, VTE risk does not return to normal until 8 to 12 weeks after cessation of COC, so it is not recommended to hold these medications before surgical procedures.8 CHC use should be included in any inpatient VTE prophylaxis algorithm, and pharmacologic thromboprophylaxis may be considered in these patients after major surgery, or orthopedic injury or surgery, or during hospitalization.

Summary and Conclusion VTE is a rare but serious complication of CHC use. While the absolute risk of VTE is low in adolescents, because of the large numbers of adolescents using these agents, VTE events in contraception users younger than 20 years account for 5 to 10% of VTE events in large population studies. An increased risk of VTE is seen not only with oral contraceptives but also the contraceptive patch and vaginal ring. Most adolescents who experience contraception-related VTE have additional VTE risk factors at the time of the event. The presence of inherited thrombophilia impacts the risk of contraceptionrelated VTE, but thrombophilia screening before contraception prescribing should be targeted only to high risk populations. Pediatric healthcare facilities as well as adult facilities need to be aware of the risk of VTE in medical and postsurgical patients who are users of hormonal contraceptives. Although the symptoms of VTE overlap with many other conditions and can be vague at time of initial presentation, clinicians need to maintain a high index of suspicion for VTE in women who are users of estrogen-containing contraceptives.

Conflict of Interest The author has no conflicts of interest to declare with regard to the content of this article.

Recognition While the absolute risk of contraception-related VTE is low, it is imperative that the medical and lay communities be aware of this potential risk. All young women need to be counseled on the risk of VTE with hormonal contraception use and to be aware of the symptoms of deep vein thrombosis and pulmonary embolism. Clinicians may not consider the risk of VTE in young healthy women using estrogencontaining contraceptive agents. Chest pain and shortness of breath are common symptoms with a variety of possible causes. As well, lower extremity deep vein thrombosis can present initially as isolated back or buttock pain, several Seminars in Thrombosis & Hemostasis

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Contraception and VTE in Adolescents

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Contraception-related venous thromboembolism in adolescents.

Venous thromboembolism (VTE) is a rare but serious complication of combined hormonal contraception. While the absolute risk of VTE is low in adolescen...
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