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A Review of Hormonal Contraception and Venous Thromboembolism in Adolescents

      Abstract

      Background

      The number of adolescents who are prescribed hormonal contraception (HC) for contraceptive and noncontraceptive indications is increasing. Approximately 1 of 4 female adolescents will use some form of HC by age 19 years. Venous thromboembolism (VTE) is a rare, but life-threatening complication associated with HC use. Although adolescents aged 15 to 19 years have the lowest absolute HC-associated VTE risk, they still account for 5.9% of HC-associated VTE. The absolute HC-associated VTE risk for those younger than 15 years of age is not well described.

      Objective

      The objectives of this report are to describe the current literature regarding HC-associated VTE in adolescents, to review the coagulation cascade and in vivo coagulation, to highlight differences between the adolescent and adult coagulation profiles, to discuss coagulation profile changes related to HC use, and to identify knowledge deficits for future study.

      Conclusion

      The mechanisms and confounding variables that lead to HC-associated VTE in all adolescents are not well understood because many large HC studies exclude female adolescents younger than 18 years of age. Because of the paucity of data in this age group, observational studies and randomized controlled trials of VTE risk in adolescents on varying forms of HC are needed. Studies should include female adolescents across the entire adolescent age span (12-21 years) to better understand HC-associated VTE risk in this population.

      Key Words

      Introduction

      Hormonal contraception (HC) is commonly used for contraceptive and noncontraceptive indications in women of all ages, and the number of adolescents prescribed these methods is increasing.

      Ehrlich E, Gibson TB, Mark TL: Trends in prescriptions for oral contraceptives among U.S. teenagers. Truven Health Analytics, March 2011. Available: http://truvenhealth.com/portals/0/assets/ACRS_11225_0712_OralContraceptives_RB_Web.pdf. Accessed May 19, 2014.

      The 2013 Centers for Disease Control and Prevention Youth Risk Behavior Surveillance survey found that 46.8% of current 9th to 12th graders reported a personal history of sexual activity.
      • Kann L.
      • Kinchen S.
      • Shanklin S.L.
      • et al.
      Youth risk behavior surveillance - United States, 2013.
      Among female adolescents aged 15 to 19 years, the 2006 to 2010 National Survey of Family Growth found that approximately 50% of female respondents “who had sex during the interview month” used a highly effective HC method.
      Centers for Disease Control and Prevention
      Sexual experience and contraceptive use among female teens—United States, 1995, 2002, and 2006-2010.
      With the mean age of menarche ranging from 12 to 13 years,
      • Sun S.S.
      • Schubert C.M.
      • Chumlea W.C.
      • et al.
      National estimates of the timing of sexual maturation and racial differences among US children.
      many female adolescents younger than 15 years of age are also prescribed HC. In fact, commercial data from 2002 to 2009 showed that approximately 4% of 13-year-old adolescents and 7% of 14-year-old adolescents filled oral contraceptive pill (OCP) prescriptions.

      Ehrlich E, Gibson TB, Mark TL: Trends in prescriptions for oral contraceptives among U.S. teenagers. Truven Health Analytics, March 2011. Available: http://truvenhealth.com/portals/0/assets/ACRS_11225_0712_OralContraceptives_RB_Web.pdf. Accessed May 19, 2014.

      Adolescent HC use is also increasing because of numerous noncontraceptive medical applications.
      • Schindler A.E.
      Non-contraceptive benefits of oral hormonal contraceptives.
      • Caserta D.
      • Ralli E.
      • Matteucci E.
      • et al.
      Combined oral contraceptives: health benefits beyond contraception.
      • Varma R.
      • Sinha D.
      • Gupta J.K.
      Non-contraceptive uses of levonorgestrel-releasing hormone system (LNG-IUS) - a systematic enquiry and overview.
      Many gynecologic disorders, including heavy menstrual bleeding, dysmenorrhea, premenstrual syndrome/premenstrual dysmorphic disorder, polycystic ovary syndrome, uterine fibroid tumors, and endometriosis/adenomyosis, have all been effectively treated with HC.
      Venous thromboembolism (VTE) is a rare, but life-threatening complication of HC use. The association of VTE with the use of HC was first described in the 1960s through a series of case reports, starting with a nurse who suffered a pulmonary embolism in the setting of combined oral contraceptive (COC) use.
      • Tyler E.T.
      Oral contraception and venous thrombosis.
      Relative HC-associated VTE risk is highest in the first year of use, and particularly in the first 6 months. This risk does not increase with continued HC use. If HC is withdrawn and restarted at a later date, the assumed VTE risk is similar to that of the first-time use.
      • Böttiger L.E.
      • Westerholm B.
      Oral contraceptives and thromboembolic disease: Swedish experience.
      • Suissa S.
      • Blais L.
      • Spitzer W.O.
      • et al.
      First-time use of newer oral contraceptives and the risk of venous thromboembolism.
      • Farley T.M.
      • Meirik O.
      • Marmot M.G.
      • et al.
      Oral contraceptives and risk of venous thromboembolism: impact of duration of use.
      • Suissa S.
      • Spitzer W.O.
      • Rainville B.
      • et al.
      Recurrent use of newer oral contraceptives and the risk of venous thromboembolism.
      This is important to note, because adolescents are not only more likely to be new HC users, they are also more likely to stop and subsequently resume HC compared with women older than 20 years of age.
      • O'Neil-Callahan M.
      • Peipert J.F.
      • Zhao Q.
      • et al.
      Twenty-four-month continuation of reversible contraception.
      Approximately 35% of adolescents who are prescribed OCPs will stop and subsequently resume use, and 40% of those adolescents will stop and restart OCPs a second time.
      • Zibners A.
      • Cromer B.A.
      • Hayes J.
      Comparison of continuation rates for hormonal contraception among adolescents.
      Increasing age continues to be a significant factor for absolute VTE risk in HC users. A large Danish national cohort study, which included more than 10 million woman-years, showed that adolescents aged 15 to 19 years had the lowest incidence of VTE of 1.84 per 10,000 exposure years than any other age group (ranging from 20 to 49 years).
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      The literature consistently reports the lowest VTE event per 10,000 exposure years in this age group.
      • Anderson Jr., F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study.
      • Nordstrom M.
      • Lindblad B.
      • Bergqvist D.
      • et al.
      A prospective study of the incidence of deep-vein thrombosis within a defined urban population.
      • Silverstein M.D.
      • Heit J.A.
      • Mohr D.N.
      • et al.
      Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
      • Oger E.
      Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale.
      • Lidegaard O.
      • Nielsen L.H.
      • Skovlund C.W.
      • et al.
      Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9.
      Even with the lowest VTE risk, a large Danish cohort study found that up to 5.9% of HC-related VTEs occur in patients aged 15 to 19 years of age.
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      Because of the limited number of studies, a paucity of epidemiologic data exist about HC-associated VTE risk in adolescents younger than age 18 years and even less is available for adolescents younger than 15 years of age. A better understanding of the mechanisms and confounding variables associated with HC-associated VTE formation across the entire adolescent age span (12-21 years) is necessary to help prevent this potentially life-threatening complication.
      The objectives of this report are to describe the current literature regarding HC-associated VTE in adolescents, to review the coagulation cascade and in vivo coagulation, to highlight differences between the adolescent and adult coagulation profiles, to discuss coagulation profile changes related to HC use, and to identify knowledge deficits that need to be addressed.

      Materials and Methods

      Medline via PubMed was searched for studies published through May 2014 using the following key words in various combinations as text words: (“hormonal contraception” or “hormonal contraceptive” or “hormonal contraceptives” or “hormonal” or “contraception” or “contraceptive”) and (“venous thromboembolism” or “thromboembolism” or “thrombus” or “thrombosis” or “clot”) and (“adolescent” or “pediatric” or “child” or “teenagers”) and (“coagulation” or “thrombophilia” or “prothrombotic” or “procoagulant” or “anticoagulant” or “protein C” or “protein S” or “antithrombin” or “activated protein C resistance” or “prothrombin” or “thrombin” or “fibrinogen” or “factor V” or “factor VII” or “factor VIII”) and (“chronic medical conditions” or “obesity” or “obese” or “overweight” or “cancer” or “oncology” or “polycystic ovary syndrome” or “epilepsy” or “headache”). Reference lists from articles identified using the systematic search were examined to identify other potential studies. Initial decisions to include or exclude studies were focused on the study title. Subsequent decisions were then centered on the abstract and the full body text. Any study that pertained to our age group of focus and was related to HC use and associated VTE was included. In Table 1 the included studies and level of current evidence are summarized.
      Table 1Existing Literature on VTE and Hormonal Contraception in Adolescents
      ReferenceStudy typeAge Range, yearsHormonal ContraceptivePrimary Outcome Variable
      Vandenbroucke et al
      • Vandenbroucke J.P.
      • Koster T.
      • Briet E.
      • et al.
      Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor-V Leiden mutation.
      Case control15-49OCPVTE with factor V Leiden mutation
      Bloemenkamp et al
      • Bloemenkamp K.W.
      • Rosendaal F.R.
      • Helmerhorst F.M.
      • et al.
      Enhancement by factor-V Leiden mutation of risk of deep-vein thrombosis associated with oral-contraceptives containing 3rd-generation progestagen.
      Case control15-49Second-/third-gen. COCVTE with factor V Leiden mutation
      Suissa et al
      • Suissa S.
      • Blais L.
      • Spitzer W.O.
      • et al.
      First-time use of newer oral contraceptives and the risk of venous thromboembolism.
      Case control16-44Second-/third-gen. COCVTE
      Harris et al
      • Harris G.M.
      • Stendt C.L.
      • Vollenhoven B.J.
      • et al.
      Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.
      Prospective16-45Second-/third-gen. COCCoagulation markers
      Middeldorp et al
      • Middeldorp S.
      • Meijers J.C.
      • van den Ende A.E.
      • et al.
      Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study.
      Randomized, cycle-controlled18-40Second-/third-gen. COCCoagulation markers
      Suissa et al
      • Suissa S.
      • Spitzer W.O.
      • Rainville B.
      • et al.
      Recurrent use of newer oral contraceptives and the risk of venous thromboembolism.
      Case control16-44Second-/third-gen. COCVTE
      Tans et al
      • Tans G.
      • Curvers J.
      • Middeldorp S.
      • et al.
      A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways.
      Randomized, cross-over18-40Second-/third-gen. COCCoagulation markers
      Magnusdottir et al
      • Magnusdottir E.M.
      • Bjarnadottir R.I.
      • Onundarson P.T.
      • et al.
      The contraceptive vaginal ring (NuvaRing) and hemostasis: a comparative study.
      Randomized, pharmacokinetic18-40Vaginal ringVTE
      Kemmeren et al
      • Kemmeren J.M.
      • Algra A.
      • Meijers J.C.
      • et al.
      Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized trial.
      Prospective18-40Second-/third-gen. COC, POPFactor V Leiden mutation, coagulation markers
      Koenen et al
      • Koenen R.R.
      • Christella M.
      • Thomassen L.G.
      • et al.
      Effect of oral contraceptives on the anticoagulant activity of protein S in plasma.
      Case control25 (mean)Second-/third-gen. COCCoagulation markers
      Dulicek et al
      • Dulicek P.
      • Maly J.
      • Pecka M.
      • et al.
      Venous thromboembolism in young female while on oral contraceptives: high frequency of inherited thrombophilia and analysis of thrombotic events in 400 Czech women.
      Cohort17-50Second-/third-gen. COCVTE
      Lidegaard et al
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      Cohort15-49COC, POPVTE
      Lidegaard et al
      • Lidegaard O.
      • Nielsen L.H.
      • Skovlund C.W.
      • et al.
      Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9.
      Historical cohort15-49COC with drospirenoneVTE
      Pillai et al
      • Pillai P.
      • Bonny A.E.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in a pediatric institution.
      Retrospective12-21OCP, DMPA, transdermal patchVTE with thrombophilia/obesity
      COC, combined oral contraceptive pill; DMPA, depot medroxyprogesterone acetate; gen., generation; OCP, oral contraceptive pill; POP, progesterone-only oral contraceptive pill; VTE, venous thromboembolism.

      Review of the Coagulation Cascade and In Vivo Coagulation

      The coagulation cascade models the prothrombin (PT) and activated partial thromboplastin time (aPTT) as they correspond to the extrinsic and intrinsic pathway, respectively are shown in Figure 1. Although the coagulation cascade provides a means of understanding how coagulation defects might affect various laboratory investigations, it does not provide an accurate portrayal of in vivo hemostasis since clinical observations are inconsistent using this model.
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      The cellular-based hemostasis model is regarded as a more accurate representation of in vivo hemostasis and involves 3 sequential and overlapping phases: initiation, amplification, and propagation (Fig. 2).
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      • Roberts H.R.
      • Hoffman M.
      • Monroe D.M.
      A cell-based model of thrombin generation.
      Figure thumbnail gr1
      Fig. 1Review of the coagulation cascade (black and blue) and endogenous anticoagulants (red). TF, tissue factor.
      Figure thumbnail gr2
      Fig. 2The cellular-based hemostasis model. TF, tissue factor.
      Initiation of coagulation occurs at sites of vessel wall injury when plasma contacts extravascular cells, like fibroblasts, which bear tissue factor (TF). Tissue factor is an integral membrane protein and chief physiologic coagulation initiator.
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      Factor VII binds to tissue factor, forming complexes that activate factor IX and factor X. Activated factor X combines with activated factor V to form the prothrombinase complex, which produces small quantities of thrombin that then activate platelets and factor VIII during amplification.
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      Amplification of coagulation involves platelets that bind to exposed collagen fibrils via von Willebrand factor adherent to the site of vascular injury. Thrombin generated during initiation enhances platelet adhesion and activation. Platelet activation leads to release of factor V and activation of factors V, VIII, and XI on the platelet surface.
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      Propagation of coagulation begins when the activated factor IX, formed during initiation, binds with activated factor VIII to form the tenase complex. The tenase complex then activates factor X on the platelet surface, which combines with activated factor V to form the prothrombinase complex. Prothrombinase complexes on the platelet surface cause the surge of thrombin production required to cleave fibrinogen into fibrin to initiate cross-linked fibrin formation.
      • Hoffman M.
      • Monroe 3rd, D.M.
      A cell-based model of hemostasis.
      The hemostatic response is balanced by a variety of endogenous anticoagulants (Fig. 1), including tissue factor pathway inhibitor, antithrombin, protein S, and activated protein C.
      • van Herrewegen F.
      • Meijers J.C.
      • Peters M.
      • et al.
      Clinical practice: the bleeding child. Part II: disorders of secondary hemostasis and fibrinolysis.
      Tissue factor pathway inhibitor regulates the initiation phase of coagulation. Antithrombin irreversibly inhibits thrombin, as well as activated factors IX, X, and XI. Protein S serves as a cofactor to activated protein C to inhibit activated factors V and VIII.
      • van Herrewegen F.
      • Meijers J.C.
      • Peters M.
      • et al.
      Clinical practice: the bleeding child. Part II: disorders of secondary hemostasis and fibrinolysis.

      Developmental Hemostasis

      The coagulation system develops with age, thus concentrations of procoagulants and endogenous anticoagulants vary throughout childhood, adolescence, and into adulthood. Studies that have compared the coagulation profiles of adolescents aged 11 to 16 years with those of adults have found significant differences.
      • Kuhle S.
      • Male C.
      • Mitchell L.
      Developmental hemostasis: pro- and anticoagulant systems during childhood.
      • Attard C.
      • van der Straaten T.
      • Karlaftis V.
      • et al.
      Developmental hemostasis: age-specific differences in the levels of hemostatic proteins.
      Differences in procoagulants include less activity of factors II, V, VII, IX, X, XI, and XII in adolescents compared with adults. Differences in endogenous anticoagulants include greater α2-macroglobulin concentrations, decreased concentration of protein C, and decreased concentration and activity of total and free protein S in adolescents.
      • Kuhle S.
      • Male C.
      • Mitchell L.
      Developmental hemostasis: pro- and anticoagulant systems during childhood.
      • Attard C.
      • van der Straaten T.
      • Karlaftis V.
      • et al.
      Developmental hemostasis: age-specific differences in the levels of hemostatic proteins.
      It is important to note that these studies included both sexes, so it is unknown if significant coagulation profile differences exist among male and female adolescents. These inherent differences in the coagulation cascade between adolescent and adult females, along with a decreased incidence of acquired VTE risk factors, such as tobacco use, diabetes mellitus, and hypertension, might account for the decreased risk of VTE in adolescents.

      Coagulation System Alterations Associated with HC Use

      Alterations in procoagulants and endogenous anticoagulants have been described in adult women with HC use (Fig. 3). These changes have been attributed mainly to the estrogen component of HC.
      • Tchaikovski S.N.
      • Rosing J.
      Mechanisms of estrogen-induced venous thromboembolism.
      Figure thumbnail gr3
      Fig. 3Coagulation profile changes associated with combined hormonal contraceptive use. AT, antithrombin; α1-AT, alpha 1-antitrypsin; ApSA, activated protein C -independent protein S activity; α2-M, alpha 2-macroglobulin; PCI, protein C inhibitor; PF 1 + 2, prothrombin fragment 1+2; TFPI, tissue factor pathway inhibitor.
      Procoagulants factors II, VII, X, fibrinogen, and prothrombin fragment 1+2, a marker of thrombin generation, have all been shown to be significantly increased with second- and third-generation COCs. Notably, the increases in factor II and factor VII are significantly greater with the use of third-generation COCs compared with second-generation COCs.
      • Middeldorp S.
      • Meijers J.C.
      • van den Ende A.E.
      • et al.
      Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study.
      Furthermore, only third-generation COCs significantly increase plasma concentrations of factor VIII and decrease concentrations of factor V compared with controls.
      Endogenous anticoagulant alterations noted with HCs include significant decreases in antithrombin activity and tissue factor pathway inhibitor activity and concentration.
      • Harris G.M.
      • Stendt C.L.
      • Vollenhoven B.J.
      • et al.
      Decreased plasma tissue factor pathway inhibitor in women taking combined oral contraceptives.
      • Tans G.
      • Curvers J.
      • Middeldorp S.
      • et al.
      A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways.
      Significant decreases in total and free protein S concentrations and significant decreases in activated protein C-independent protein S activity have also been shown.
      • Koenen R.R.
      • Christella M.
      • Thomassen L.G.
      • et al.
      Effect of oral contraceptives on the anticoagulant activity of protein S in plasma.
      Although protein S serves mainly as an activated protein C cofactor, it has also been shown to have an activated protein C-independent ability to inhibit the prothrombinase and tenase complexes by binding directly to activated factors V, VIII, or X.
      • van Wijnen M.
      • Stam J.G.
      • van't Veer C.
      • et al.
      The interaction of protein S with the phospholipid surface is essential for the activated protein C-independent activity of protein S.
      Although a mild increase in the concentration and activity of protein C has also been noted with HC use, an increase in 3 major protein C inhibitors (protein C inhibitor, α1-antitrypsin, and α2-macroglobulin) have all been described, which likely mitigate the effects of increased protein C.
      • Tans G.
      • Curvers J.
      • Middeldorp S.
      • et al.
      A randomized cross-over study on the effects of levonorgestrel- and desogestrel-containing oral contraceptives on the anticoagulant pathways.
      • Kemmeren J.M.
      • Algra A.
      • Meijers J.C.
      • et al.
      Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized trial.
      Large cohort studies, and small crossover studies, have attributed differences between COC generations in coagulation profile alterations to the varying progestin agents and their interaction with estrogen.
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      • Lidegaard O.
      • Nielsen L.H.
      • Skovlund C.W.
      • et al.
      Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9.
      • Middeldorp S.
      • Meijers J.C.
      • van den Ende A.E.
      • et al.
      Effects on coagulation of levonorgestrel- and desogestrel-containing low dose oral contraceptives: a cross-over study.
      COCs containing third-generation progestins, like desogestrel or gestodene, and the “fourth-generation” drospirenone have a two-to threefold greater relative VTE risk than COCs containing second-generation progestins like levonorgesterel.
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      • Lidegaard O.
      • Nielsen L.H.
      • Skovlund C.W.
      • et al.
      Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9.
      • Jick H.
      • Jick S.S.
      • Gurewich V.
      • et al.
      Risk of idiopathic cardiovascular death and nonfatal venous thromboembolism in women using oral-contraceptives with differing progestagen components.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in adolescents.
      Activated protein C resistance has been suggested as an explanation for this increased VTE risk. Studies have shown increased activated protein C resistance in HC users compared with nonusers. In addition, significantly greater activated protein C resistance has been observed in third-generation COC users compared with second-generation COC users.
      • Koenen R.R.
      • Christella M.
      • Thomassen L.G.
      • et al.
      Effect of oral contraceptives on the anticoagulant activity of protein S in plasma.
      • Tchaikovski S.N.
      • Rosing J.
      Mechanisms of estrogen-induced venous thromboembolism.
      It is theorized that HC-related increases in protein C inhibitors and decreases in total and free protein S concentrations contribute to this phenomenon. Protein S serves as an activated protein C cofactor in the process of inactivating factor Va and factor VIIIa.
      • Rosing J.
      • Hoekema L.
      • Nicolaes G.A.
      • et al.
      Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C.
      Thus, significantly lower protein S concentrations associated with HC use would naturally result in decreased activated protein C activity.
      Combined vaginal contraceptive rings containing etonogestrel and ethinyl estradiol have also been associated with VTE and cerebral venous sinus thrombosis.
      • Bjarnadottir R.I.
      • Tuppurainen M.
      • Killick S.R.
      Comparison of cycle control with a combined contraceptive vaginal ring and oral levonorgestrel/ethinyl estradiol.
      • Oddsson K.
      • Leifels-Fischer B.
      • de Melo N.R.
      • et al.
      Efficacy and safety of a contraceptive vaginal ring (NuvaRing) compared with a combined oral contraceptive: a 1-year randomized trial.
      • Ahrendt H.J.
      • Nisand I.
      • Bastianelli C.
      • et al.
      Efficacy, acceptability and tolerability of the combined contraceptive ring, NuvaRing, compared with an oral contraceptive containing 30 microg of ethinyl estradiol and 3 mg of drospirenone.
      • Roumen F.J.
      • op ten Berg M.M.
      • Hoomans E.H.
      The combined contraceptive vaginal ring (NuvaRing): first experience in daily clinical practice in the Netherlands.
      • Lopez L.M.
      • Grimes D.A.
      • Gallo M.F.
      • et al.
      Skin patch and vaginal ring versus combined oral contraceptives for contraception.
      • Kolacki C.
      • Rocco V.
      The combined vaginal contraceptive ring, NuvaRing, and cerebral venous sinus thrombosis: a case report and review of the literature.
      Factor VII level has been shown to be significantly increased in contraceptive ring users compared with second-generation COC users.
      • Magnusdottir E.M.
      • Bjarnadottir R.I.
      • Onundarson P.T.
      • et al.
      The contraceptive vaginal ring (NuvaRing) and hemostasis: a comparative study.
      Fibrinogen levels and prothrombin fragment 1+2 have also shown to be higher during contraceptive ring use.
      • Kemmeren J.M.
      • Algra A.
      • Meijers J.C.
      • et al.
      Effect of second- and third-generation oral contraceptives on the protein C system in the absence or presence of the factor V Leiden mutation: a randomized trial.
      Importantly, our literature search identified no studies that evaluated HC-associated coagulation profile changes in patients younger than the age of 18 years. As such, it is not known if younger HC users experience the same procoagulant and anticoagulant changes that have been noted in adults.

      Confounding Risk Factors for HC-associated VTE

      A variety of risk factors, such as inherited thrombophilia, obesity, and pregnancy, confer increased risk of VTE in women of all ages (Table 2).
      • Varga E.
      Inherited thrombophilia: key points for genetic counseling.
      • Robertson L.
      • Wu O.
      • Langhorne P.
      • et al.
      Thrombophilia in pregnancy: a systematic review.
      • Pomp E.R.
      • Lenselink A.M.
      • Rosendaal F.R.
      • et al.
      Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study.
      • McColl M.D.
      • Ramsay J.E.
      • Tait R.C.
      • et al.
      Risk factors for pregnancy associated venous thromboembolism.
      • Stein P.D.
      • Beemath A.
      • Olson R.E.
      Obesity as a risk factor in venous thromboembolism.
      • Abdollahi M.
      • Cushman M.
      • Rosendaal F.R.
      Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use.
      • Heit J.A.
      • Kobbervig C.E.
      • James A.H.
      • et al.
      Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study.
      Adolescents who develop VTE while using HCs often have additional acquired or inheritable VTE risk factors.
      • Dulicek P.
      • Maly J.
      • Pecka M.
      • et al.
      Venous thromboembolism in young female while on oral contraceptives: high frequency of inherited thrombophilia and analysis of thrombotic events in 400 Czech women.
      • Pillai P.
      • Bonny A.E.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in a pediatric institution.
      As many as 96% of women aged 12 to 21 years with HC-associated VTE have at least 1 additional VTE risk factor, and 42% have 2 or more risk factors.
      • Pillai P.
      • Bonny A.E.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in a pediatric institution.
      Table 2VTE Risk Factors in Women
      Risk FactorRelative Fold Increase in VTE Risk
      Independent of hormonal contraceptive use.
      Obesity
       All ages2-3
       Younger than 40 years6
      Thrombophilia
       Homozygous factor V Leiden80
       Heterozygous factor V Leiden3-7
       Heterozygous prothrombin 20210A mutation2-3
       Compound heterozygous factor V Leiden and prothrombin 20210A mutation20
       Heterozygous protein C deficiency7-10
       Heterozygous protein S deficiency7-10
       Heterozygous antithrombin deficiency10-20
       Pregnancy3-5
      Pregnancy with thrombophilia
       Homozygous factor V Leiden34
       Heterozygous factor V Leiden8-25
       Homozygous prothrombin 20210A mutation26
       Heterozygous Prothrombin 20210A mutation7-15
       Heterozygous for factor V Leiden and prothrombin 20210A mutation100
       Protein C deficiency5
       Protein S deficiency3
       Antithrombin deficiency5
      Immediate postpartum (<3 months)20-100
      Risk varies based on number of weeks postpartum.
      Family History of VTE3-4
      Hormonal replacement therapy2-4
      Hormonal replacement therapy with thrombophilia
       Heterozygous factor V Leiden13-15
      VTE, venous thromboembolism.
      Independent of hormonal contraceptive use.
      Risk varies based on number of weeks postpartum.
      Inherited thrombophilias, such as factor V Leiden mutation, prothrombin 20210A mutation, and deficiencies in endogenous anticoagulants, affect HC-associated VTE risk among all age groups. One large study of women aged 17 to 50 years found that 43% of HC-related VTE were associated with a heritable thrombophilia.
      • Dulicek P.
      • Maly J.
      • Pecka M.
      • et al.
      Venous thromboembolism in young female while on oral contraceptives: high frequency of inherited thrombophilia and analysis of thrombotic events in 400 Czech women.
      Interestingly, inherited thrombophilias were significantly more prevalent as a confounding VTE risk factor than any other risk factor in this study (body mass index data were not available for evaluation), and the incidence of thrombophilia did not differ between women younger or older than 26 years.
      • Dulicek P.
      • Maly J.
      • Pecka M.
      • et al.
      Venous thromboembolism in young female while on oral contraceptives: high frequency of inherited thrombophilia and analysis of thrombotic events in 400 Czech women.
      The effect of factor V Leiden mutations on the risk for developing HC-associated VTE has been well described. A 20- to 30-fold increased VTE risk has been shown in women heterozygous for the factor V Leiden mutation who were using OCPs compared with women with the mutation who were not using OCPs.
      • Vandenbroucke J.P.
      • Koster T.
      • Briet E.
      • et al.
      Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor-V Leiden mutation.
      There is evidence that the risk might be even higher in women who receive third-generation COCs.
      • Bloemenkamp K.W.
      • Rosendaal F.R.
      • Helmerhorst F.M.
      • et al.
      Enhancement by factor-V Leiden mutation of risk of deep-vein thrombosis associated with oral-contraceptives containing 3rd-generation progestagen.
      In women homozygous for the factor V Leiden mutation, there is a 50- to 100-fold increased risk of HC-associated VTE development.
      • Rosendaal F.R.
      • Koster T.
      • Vandenbroucke J.P.
      • et al.
      High-risk of thrombosis in patients homozygous for factor-V Leiden (activated protein-C resistance).
      Presence of the prothrombin 20210A mutation has also been noted to confer a 16-fold increased risk of VTE formation in women who use COCs compared with nonusers.
      • Martinelli I.
      • Taioli E.
      • Bucciarelli P.
      • et al.
      Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.
      In addition, inherited deficiencies in the endogenous anticoagulants, including protein C, protein S, and antithrombin, also confer a greater relative risk of developing spontaneous VTE.
      • Simioni P.
      • Sanson B.J.
      • Prandoni P.
      • et al.
      Incidence of venous thromboembolism in families with inherited thrombophilia.
      A large retrospective cohort study found that women with deficiencies in these natural anticoagulants were at even higher risk for VTE development with COC use than those with factor V Leiden or prothrombin 20210A mutations.
      • Simioni P.
      • Sanson B.J.
      • Prandoni P.
      • et al.
      Incidence of venous thromboembolism in families with inherited thrombophilia.
      Chronic medical conditions including cardiovascular disease, malignancy, and neuromuscular disease are commonly found in pediatric VTE diagnoses and might increase HC-associated VTE risk.
      • Setty B.A.
      • O'Brien S.H.
      • Kerlin B.A.
      Pediatric venous thromboembolism in the United States: a tertiary care complication of chronic diseases.
      Medically complicated adolescents are often prescribed HC because HC-associated VTE risk is generally outweighed by pregnancy-associated risks.
      • Heroux K.
      Contraceptive choices in medically ill adolescents.
      Menstrual suppression is often sought for adolescent women with various chronic medical conditions (eg, cancer, bleeding disorders, catamenial epilepsy, catamenial headaches, and developmental delay).
      • Bedaiwy M.A.
      • Abou-Setta A.M.
      • Desai N.
      • et al.
      Gonadotropin-releasing hormone analog cotreatment for preservation of ovarian function during gonadotoxic chemotherapy: a systematic review and meta-analysis.
      • Case A.M.
      • Reid R.L.
      Effects of the menstrual cycle on medical disorders.
      • Servais L.
      • Jacques D.
      • Leach R.
      • et al.
      Contraception of women with intellectual disability: prevalence and determinants.
      • Archer D.F.
      Menstrual-cycle-related symptoms: a review of the rationale for continuous use of oral contraceptives.
      Many chronic medical conditions bear an increased VTE risk at baseline, and adolescents with chronic medical conditions are often excluded from HC clinical studies. Thus, an accurate understanding of the true HC-associated VTE risk for adolescents with chronic medical conditions is currently lacking.
      Obesity is an independent VTE risk factor and is commonly observed in association with HC-associated VTE in adolescents.
      • Pillai P.
      • Bonny A.E.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in a pediatric institution.
      More than 31% of children aged 2 to 19 years in the United States are considered overweight, almost 17% are considered obese, and these numbers continue to increase.
      • Ogden C.L.
      • Carroll M.D.
      • Kit B.K.
      • et al.
      Prevalence of obesity in the United States, 2009-2010.
      One single-institution pediatric study that involved 26 HC-associated VTEs revealed that obesity was the most common additional VTE risk factor in women aged 12 to 21 years who developed a VTE while using HCs.
      • Pillai P.
      • Bonny A.E.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in a pediatric institution.
      Obesity has been associated with alterations in the procoagulant system, including increases in factors VII, VIII, XII, and fibrinogen.
      • Abdollahi M.
      • Cushman M.
      • Rosendaal F.R.
      Obesity: risk of venous thrombosis and the interaction with coagulation factor levels and oral contraceptive use.
      Obese women have twice the VTE risk of the general population, and obese women using HCs have up to a 10-fold increased VTE risk compared with the general population.
      • Murthy A.S.
      Obesity and contraception: emerging issues.
      Obesity is also associated with earlier onset of puberty, which could result in even earlier use of HC agents.
      • Anderson S.E.
      • Dallal G.E.
      • Must A.
      Relative weight and race influence average age at menarche: results from two nationally representative surveys of US girls studied 25 years apart.
      It is difficult to truly understand the HC-associated VTE risk in all overweight and obese adolescents because women younger than 18 years of age are often excluded from HC studies and those younger than 16 years of age are rarely included.

      Summary and Conclusion

      VTE is a rare but serious complication associated with HC use. Among HC users, adolescents are generally considered a low-risk group for VTE, yet up to 5.9% of HC-associated VTEs are seen in adolescents 15 to 19 years of age.
      • Lidegaard O.
      • Lokkegaard E.
      • Svendsen A.L.
      • et al.
      Hormonal contraception and risk of venous thromboembolism: national follow-up study.
      The absolute HC-associated VTE risk for those younger than 15 years of age is not well described.
      Inherent differences between adolescents and adults exist in concentrations of procoagulants and endogenous anticoagulants. In general, adolescents 11 to 16 years of age exhibit decreased procoagulants, increased endogenous anticoagulant inhibitors, and decreased endogenous anticoagulants compared with adults.
      • O'Brien S.H.
      Contraception-related venous thromboembolism in adolescents.
      • Rosing J.
      • Hoekema L.
      • Nicolaes G.A.
      • et al.
      Effects of protein S and factor Xa on peptide bond cleavages during inactivation of factor Va and factor VaR506Q by activated protein C.
      These coagulation differences, in conjunction with decreased incidence of acquired VTE risk factors such as tobacco use, diabetes mellitus, and hypertension might account for the decreased risk of HC-associated VTE risk in adolescents.
      In adult populations, a variety of studies have described HC-associated alterations in procoagulants and endogenous anticoagulants. Importantly, our literature search identified no studies that evaluated HC-associated coagulation profile changes in patients younger than the age of 18 years. As such, it is not known if younger HC users experience the same coagulation changes as noted in adults. Based on developmental changes that occur in the coagulation system throughout childhood, adolescence, and into adulthood, we cannot assume that adult data provide a good proxy for HC-associated coagulation system alterations.
      Obese adolescents and those with chronic medical conditions constitute unique populations that require additional scrutiny. Obesity rates continue to increase among pediatric patients in the United States. Obesity is associated with increased procoagulant levels and earlier puberty, and as such, the potential for earlier HC exposure. Chronically ill female adolescents often require HC for various reasons, which increases any existing VTE risk secondary to their underlying condition. Studies that include obese adolescents and those with chronic medical conditions are required to better understand the HC-associated VTE risk in these populations.
      In conclusion, HC use is common in healthy adolescents and those with complicated medical histories. VTE is a rare but serious complication associated with HC use. Studies that examined HC-associated VTE risk have not consistently included female participants across the entire adolescent age span (12-21 years). As such, knowledge deficits preclude a proper understanding of the actual HC-associated VTE risk in this population.
      Future pediatric-specific HC studies should include adolescents across the entire adolescent age span (12-21 years). Because of the paucity of data in this age group, observational studies and randomized controlled trials of VTE risk in adolescents taking varying forms of HC are needed. In addition, studies on the effect of age and pubertal development on HC-associated coagulation parameter changes would further aid to characterize VTE risk in adolescents.

      Acknowledgments

      The authors acknowledge Dr Elizabeth Kudron for her thoughtful review of a draft of this report, and Hannah Lange, MPH, for her editorial assistance.

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