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Levonorgestrel intrauterine system: bleeding disorders and anticoagulant therapy
Contraception 75 (2007) S123 – S129
Review article
Levonorgestrel intrauterine system: bleeding disorders and anticoagulant therapy Rezan A. Kadir4, Claudia Chi Department of Obstetrics and Gynaecology and Katharine Dormandy Haemophilia Center and Haemostasis Unit, Royal Free Hospital, NW3 2QG London, UK Received 27 December 2006; accepted 19 January 2007
Abstract Hemostatic disorders in women are frequently associated with long-standing menorrhagia. This leads to significant morbidity and adversely affects quality of life. Management of these women poses a particular challenge; medical treatments may be contraindicated, and surgery carries additional risks. The levonorgestrel intrauterine system (LNG-IUS) has been shown to be highly effective in reducing menstrual blood loss in women with normal coagulation. It is also a reliable and reversible contraceptive. Data on the use of this system in women with bleeding disorders or those receiving anticoagulant therapy are limited. Analysis of data from four reported studies suggests that LNG-IUS is a viable and safe option for the management of menorrhagia in these women. Whether the underlying hemostatic disorders lead to a shorter duration of action or prolonged irregular bleeding/spotting post insertion is unknown and requires large prospective studies. Proper counselling remains crucial for patients’ satisfaction. D 2007 Elsevier Inc. All rights reserved. Keywords: Levonorgestrel intrauterine system; Bleeding disorders; Anticoagulant therapy
1. Introduction Disorders of hemostasis are frequently associated with bleeding complications. Women appear to be disproportionately affected with these disorders, and menorrhagia is the most common bleeding symptom. Management of menorrhagia in these women may pose many challenges to clinicians. They may be refractory to many medical treatments, whilst other pharmacological agents can be contraindicated for use. Furthermore, surgical treatment carries additional risks of bleeding or thrombotic complications. The levonorgestrel intrauterine system (LNG-IUS), primarily developed as a contraceptive device, is now increasingly used for the treatment of menorrhagia. With a high efficacy in reducing menstrual blood loss and minimal systemic side effects, it may provide a promising alternate treatment option for these women. This review aims to discuss the magnitude of menstrual disorders affecting women with inherited bleeding disorders
4 Corresponding author. Tel.: +44 020 77940500x35317; fax: +44 020 7830 2799. E-mail address: [email protected] (R.A. Kadir). 0010-7824/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2007.01.005
and those receiving anticoagulant therapy. It also addresses the difficulties in treating these women. Finally, it examines the available evidence for the use and effectiveness of LNGIUS in the treatment of menorrhagia and the possible benefits for other gynecological problems. Areas for future research are also explored. 2. Inherited bleeding disorders Inherited bleeding disorders in women are more common than previously suspected. Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of approximately 1% in the general population [1,2]. It is generally inherited in an autosomal manner, thus it affects both males and females equally. However, more women with VWD are symptomatic due to the hemostatic challenges of childbirth and monthly menstruation. In the United Kingdom Haemophiila Center Doctors’ Organisation 2005 registry, women accounted for over 60% of the patient registered with VWD. VWD is classified into three main types according to whether the defect in von Willebrand factor (VWF) is quantitative (Types 1 and 3) or qualitative (Type 2). Type 1 is the most common, accounting for
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around 70% of all cases and is characterized by a partial deficiency in VWF. Type 3 involves a near or complete absent of VWF and is therefore severe. This is a rare disorder with a prevalence ranging from 0.1 to 5.3 per million [3]. There are four subtypes (2A, 2B, 2N, 2M) of Type 2 VWD. Type 1 and most Type 2 are transmitted as an autosomal dominant trait, whilst Type 3 and 2N are inherited in a recessive manner. Hemophilia A and B are the most common severe inherited bleeding disorder. They result from deficiencies of coagulation factors VIII and IX, respectively. Their pattern of inheritance is X-linked recessive, hence, men inherit the condition and women are affected as carriers. Carriers of hemophilia are expected to have clotting factor levels around 50% of normal (normal range, 50–150 IU/dL). However, a significant number of carriers have a low factor level and a bleeding tendency. In a study by Plug et al. [4], 27.5% of carriers had a clotting factor level of V 40 IU/dL. These carriers, as well as those with factor levels between 41 and 60 IU/dL, had an increased risk of bleeding compared to noncarriers. A deficiency in other plasma clotting factors (fibrinogen; prothrombin; factor V, VII, X, XI, XIII) or a quantitative or qualitative defect in platelets can also cause bleeding symptoms of varying severity. These rarer coagulation disorders are generally inherited as autosomal recessive traits with severe forms expressed in homozygotes or compound heterozygotes. 3. Menorrhagia in women with hemostatic disorders Disorders of hemostasis are commonly associated with excessive menstrual blood loss. In a survey of 99 women with Type 1 VWD from four hemophilia centers in the United States, 79% reported their periods to be heavy, 71% required medical attention and 13% required hysterectomy for control of menorrhagia [5]. In a study by Ragni et al [6], 93% of 38 women with VWD suffered from heavy menstruation. Menorrhagia was the most common initial bleeding symptom leading to the diagnosis of the disease in 53% of them. In an international survey of 44 women with more severe forms of VWD, 80% had at least one episode of severe menorrhagia requiring blood product therapy [7]. In our center, using the pictorial blood assessment chart (PBAC) [8], menorrhagia (defined by a score of more than 100) was reported in 74%, 57% and 59% of 66 women with VWD, 30 carriers of hemophilia and 20 Factor XI (FXI)deficient women, respectively, compared to 29% in the agematched control group [9]. Women with these disorders also had significantly longer periods (25% bled for more than 8 days compared to only 4% in the control group) and more episodes of flooding and passage of clots [9]. Menorrhagia is a long-standing problem for these women and usually starts from menarche. Menorrhagia since menarche was reported in 65% of women diagnosed with a bleeding disorder, compared to only 9% in those with normal coagulation
[10]. Heavy menstruation has also been reported in women with platelet disorders or a deficiency in prothrombin, fibrinogen, factor V, factor VII, factor X or factor XIII. In a review of published series, menorrhagia was reported in 35– 98% of women with these disorders [11]. Iron deficiency anemia is consequently prevalent among women with bleeding disorders. A past or present history of anemia was reported in 64% of 81 menstruating women with Type 1 VWD, compared with 34% of 150 menstruating controls [5]. There is also a high rate of surgical interventions for menorrhagia, including hysterectomy. A hysterectomy rate of 23–26% has been reported among women with VWD [7,12]. Hysterectomy is often performed at a relatively young age and prior to the diagnosis of the bleeding disorder. There has been a report of hysterectomy as early as 14 years of age [7]. Menstruation also has a significant negative impact on the quality of life of these women. A striking difference in health-related quality of life has been reported between males and females with VWD, with a significantly poorer score in women [13]. It is likely that this burden of morbidity reflects the adverse effects of menorrhagia. Over a third of women with inherited bleeding disorders had to cut down the time spent at work and other activities or accomplished less as a result of their menstruation [14]. Data on menstruation and the prevalence of menorrhagia in women on anticoagulant therapy is very limited. In a small study by van Eijkeren et al. [15], the mean menstrual blood loss measured by the alkaline hematin method was 98 mL (range, 9–239 m/L) in 11 women receiving anticoagulant therapy; five (45%) had menorrhagia (menstrual blood loss of more than 80 mL). Of the six women with normal menstrual loss, two had losses in the high-normal range (60–80 mL). In our center, nine (82%) of the 11 women on anticoagulant therapy had menorrhagia defined by a pictorial blood assessment chart score of greater than 100 (ongoing study). Five women developed intermenstrual bleeding, and six women reported adverse effect on their quality of life during menstruation after the start of their anticoagulant therapy. Choices for contraception and the treatment options of menorrhagia in women on anticoagulant therapy are limited. Combined oral contraceptives are usually contraindicated because of their increased risk of thromboembolic disorders. Copper-containing intrauterine devices are associated with a further increase in menstrual loss. Many clinicians are also very reluctant to use antifibrinolytics in women with a thrombotic tendency. Progestogens alone are therefore the treatment of choice for these women. 4. Levonorgestrel intrauterine system for treatment of menorrhagia in women with hemostatic disorders The LNG-IUS is well established as an effective, longacting and reversible contraceptive. It is associated with a significant reduction in menstrual blood loss as early as the
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first period after insertion [16,17]. It therefore provides an effective treatment modality for menorrhagia and an alternative to surgical interventions for many women. Data regarding the use of LNG-IUS in women with hemostatic disorders is very limited. Literature search revealed only four studies including a total of 69 women [18 – 21]. In our center, the LNG-IUS was used in 16 women with inherited bleeding disorders (13 VWD, two FXI deficiency and one Hermansky-Pudlak syndrome) and menorrhagia not responding to various medical treatments [18]. Nine months after the insertion of the LNG-IUS, nine women became amenorrheic. In the remaining seven women, the PBAC scores decreased significantly from a median of 213 (range 98–386) to 47 (range 24–75). The hemoglobin concentrations increased significantly from a median of 12.1 (range, 8.0–13.2 g/dL) to 13.1 (range, 12.3–14) (p =.0001). No side effects were reported except irregular spotting. The duration of spotting ranged from 30–90 days (median 42 days). Prior to the insertion of the LNG-IUS, the quality of life was adversely affected in all women during their menses for at least 1 day. Nine months after insertion of the LNG-IUS, none of them had any days adversely affected by their menstruation. In another study conducted in New York, the use of LNG-IUS was associated with significant reduction in the menstrual bleeding of 13 women with inherited bleeding disorders (11 VWD, 1 carrier of hemophilia A, 1 platelet function disorder) (Ref. [21] and personal communication with P. Kouides, May 2006). Similarly, there was a significant improvement in the quality of life in all women. The median duration of spotting post insertion was 12 weeks. In one patient, the LNG-IUS was removed at 7 months for this reason. The LNG-IUS was also shown to be an effective treatment for menorrhagia in women receiving oral anticoagulation in a study by Pisoni et al. [20]. Its use was associated with a reduction of menstrual loss in 87% of 16 women receiving warfarin therapy, with a target international normalized ratio between 2.3 and 3.4. Four women became amenorrheic. In addition, there was reduction in the duration of menstruation and the number of sanitary protections used by the women. Most (75%) women felt very satisfied or satisfied with the LNG-IUS. In the study by Schaedel et al. [19], the use of LNGIUS was evaluated in women with various hemostatic disorders including bleeding and thromboembolic disorders. In this retrospective review, 86% (24/28) of the women accepted this form of treatment, including 12 women with bleeding disorders (6 thrombocytopenia, 4 VWD, 1 FXI deficiency and 1 dysfibrinoginemia) and 12 women with thromboembolic disorders, four of whom were on warfarin therapy. The discontinuation rate at 12 months was 21% (5/24). In two women, the LNG-IUS was removed within 7 days due to pain. Another woman developed transverse sinus thrombosis 1 month after LNG-IUS insertion. She was on warfarin treatment for a
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thrombotic disorder, and the LNG-IUS was removed as cautionary. There was one pregnancy with the LNG-IUS in place at 12 months. The last removal was in a woman who experienced worsening menorrhagia following an initial improvement in menstrual blood loss. Among the remaining 19 women, 12 (63%) experienced dramatic clinical improvement with reduced menstrual blood loss or amenorrhoea after the insertion of the first LNG-IUS. The duration of LNG-IUS in place in these women varied between 0.25 and 6 years (median, 4 years). However, seven (37%) women experienced a return of symptoms of varying extent after an initial clinical improvement and required a change of the LNG-IUS after 1–6 years (median duration, 3 years). All of them reported clinical improvement after having the first LNG-IUS removed and another immediately reinserted. A study assessing the long-term effect of LNG-IUS in the management of menorrhagia in women with inherited bleeding disorders is underway in our center. Our preliminary data suggest that this treatment continues to be effective at a median duration of 53 months (range, 24– 60 months) post insertion. The PBAC score of the 13 women, reviewed so far, decreased from a median of 286 (range, 165–386) prior to insertion to a median of 8 (range, 0–77) post insertion; six women were amenorrheic. Their mean hemoglobin concentration increased from 11.5 (range, 10.6–12.9) to 13.1 (range, 11.8–14.2) g/dL. All aspects of quality of life, assessed by a healthrelated quality of life questionnaire [14], were significantly better compared to pre-LNG-IUS insertion. There was one discontinuation at 12 months in a woman who wanted to conceive. Another woman required a change of her LNGIUS because of worsening mastalgia. Her symptom resolved after the replacement of the LNG-IUS.
5. Levonorgestrel intrauterine system for other gynecological problems in women with hemostatic disorders 5.1. Dysmenorrhea Dysmenorrhea is commonly experienced by women with inherited bleeding disorders. Severe or very severe pain during menstruation has been reported in 24% of women with inherited bleeding disorders, compared to 4% in the controls [14]. Nonsteroidal anti-inflammatory drugs are used successfully in the treatment of dysmenorrhea and may also reduce menstrual blood loss in women with menorrhagia. In women with bleeding disorders, especially those with a severe deficiency, this treatment may cause an increase in menstrual blood loss and other bleeding complications due to their antiplatelet effects. Therefore, their use is contraindicated in these women. The LNG-IUS has been shown to be an effective treatment for dysmenorrhea with or without endometriosis [22–25]. In an ongoing study in our center, severe
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dysmenorrhea was reported by 50% of 13 women with inherited bleeding disorders prior to the use of the LNGIUS. When reviewed at 24 months or more after insertion, none had severe dysmenorrhea.
required to establish the efficacy and safety of the LNGIUS in the treatment of these conditions before recommending its routine use.
5.2. Midcycle ovulation pain and bleeding
6. Adverse effects of the levonorgestrel intrauterine system in women with hemostatic disorders
Midcycle pain or Mittelschmerz syndrome was reported by 49% of Type 1 VWD women in a study by Kouides et al. [5]. This pain probably arises from ovulation with subsequent hemorrhage into the corpus luteum or peritoneal irritation due to bleeding from edges of a recently formed corpus luteum. Indeed, acute abdomen due to hemoperitoneum and the extension of bleeding into the broad ligament with spontaneous rupture of the corpus luteum has been reported in patients with bleeding disorders [26,27]. It is important to consider this complication, especially in women with a severe hemostatic disorder such as Type 3 VWD or Glanzmann’s thrombasthenia, before embarking on any surgical intervention. Conservative management with appropriate hemostatic agent has been reported to be successful in avoiding surgery [26]. Suppression of ovulation may be required to prevent recurrence [28]. Combined oral contraceptives are usually used for this purpose. The majority of the menstrual cycles are ovulatory in women using the LNG-IUS. It may therefore be necessary to continue the use of the combined oral contraceptive pill when the LNG-IUS is used for the treatment of menorrhagia or contraception in women with such severe bleeding disorders. 5.3. Other gynecological conditions There is currently very limited data on gynecological problems other than menorrhagia in women with hemostatic disorders. Gynecological problems, especially those manifest with bleeding such as endometriosis, fibroids and endometrial polyps or hyperplasia, were reported more frequently in women with VWD compared to controls in one survey [12]. It is possible that women with bleeding disorders are more likely to become symptomatic with these conditions because of their bleeding tendency. However, large studies are required to assess the association between bleeding disorders and these gynecological problems. The LNG-IUS has been shown to be associated with a reduction in menstrual pain and severity of the disease in women with endometriosis [25,29,30]. A decreased incidence of fibroids following LNG-IUS insertion has also been described [31]. Furthermore, LNG-IUS provides endometrial protection in women taking hormone replacement therapy [31–34], and it is now licensed for this purpose in the United Kingdom and Europe. In addition, promising research indicates regression of endometrial hyperplasia and early-stage endometrial cancer with the LNG-IUS [35–37]. Therefore, the LNG-IUS may have an extended role in managing many gynecological conditions, especially in women with high surgical risks, such as those with hemostatic disorders. However, further studies are
6.1. Complications at insertion Women with bleeding disorders are potentially at risk of bleeding at the time of insertion. Prophylactic treatment for hemostasis should be considered, especially in women with severe bleeding disorders. Women with mild disorders may not require any treatment. In the series by Kouides et al. [21], the procedure was performed without hemostatic cover in 13 women with no bleeding complications. Tranexamic acid (1 g) given 1 h prior to the procedure and continued every 6 h for 24 h is generally sufficient for the majority of women. However, liaison with the hematologist is essential, especially when other form of hemostatic agents such as desmopressin, factor concentrate or platelet transfusion is required. 6.2. Expulsion Total or partial expulsion of the IUS could be due to heavy menstrual blood loss or uterine contractions [38]. Women with hemostatic disorders have very heavy and prolonged periods [9]. Therefore, the use of tranexamic acid during insertion and the first one or two menstrual periods may reduce the risk of this complication in these women. This treatment regimen is currently practiced in our center, and so far, we have had no expulsion in over 25 women with inherited bleeding disorders. 6.3. Irregular spotting/bleeding Irregular and prolonged spotting or mild bleeding in the first 3–6 months after insertion is the main disadvantage of the LNG-IUS. This side effect is a common cause for the discontinuation of treatment. In a systematic review of five randomized controlled trials and five case series on the use of LNG-IUS for the treatment of menorrhagia, the average discontinuation rate at 12 months was 20% in the randomized trials and 17% in the case series [17]. Intermittent intermenstrual bleeding and prolonged bleeding or spotting accounted for 4% and 2% of the discontinuations, respectively. In women with hemostatic disorders, the discontinuation rate among 53 women in the three reported studies was 17% [18,19,21]. Irregular spotting was the main reason for discontinuation in only one of these women [21]. Two women in the study by Schaedel et al. [19] required removal of the original LNGIUS and insertion of a new device for this reason; the spotting settled after replacement of the LNG-IUS. Women with hemostatic disorders and menorrhagia may be more tolerant of this side effect, compared to women with normal menstruation using the LNG-IUS for contraception.
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They have long-standing menorrhagia with chronic iron deficiency anemia. They are generally satisfied with the advantages of reduced menstrual blood loss and improved general health and quality of life achieved with the LNGIUS. Irregular bleeding/spotting with the LNG-IUS was reported in all women (n = 16) in the study by Kingman et al. [18]. Their quality of life after was reported to be better despite this adverse effect. Eleven women did not feel that irregular spotting affected their life, and the remaining five were only slightly affected. Counselling on the potential changes in the bleeding pattern prior to the insertion and reassurance during the follow-up visits that the irregular bleeding will eventually stop improve patients’ acceptability [35]. 6.4. Persistent/recurrent menorrhagia Persistent or recurrent menorrhagia is another reason for treatment discontinuation. LNG-IUS induces atrophy of the endometrial epithelium for more than 5 years [39], which provides a rationale for the reduction of menstrual blood loss. In a study by Xiao et al. [38], the reduction in menstrual loss and the increase in hemoglobin concentrations continued to be significant at the 3-year followup. Similarly, in a randomized controlled trial of the LNG-IUS versus hysterectomy for the treatment of menorrhagia, 48% (57/119) of women still had the LNG-IUS in situ 5 years after randomization with a high satisfaction rate, which was similar to hysterectomy [40]. Discontinuation due to persistent/recurrent menorrhagia was only 16%. In hemostatic disorder-related menorrhagia, data on the duration of effectiveness and rate of symptom recurrence are very limited. In the study by Schaedel et al. [19], 37% of women experienced return of symptoms after an initial clinical improvement. Replacement of the original LNG-IUS with a new device reversed the deterioration in symptoms, and all the women were satisfied with the second IUS. Although based on very limited data, clinicians should consider replacement of the LNG-IUS with another device in women who experience recurrence of heavy bleeding or irregular spotting after an initial positive response. 6.5. Ovarian cysts The use of the LNG-IUS has been reported to be associated with an increased occurrence of ovarian cysts [41–43]. Using transvaginal ultrasound examination, ovarian cysts have been found in 17.5% and 21.5% of women after 6 and 12 months, respectively, of LNG-IUS use [43]. The cysts are asymptomatic and relatively small in size. The majority of these cysts are functional with a high rate of spontaneous resolution. However, there is a potential risk of hemorrhage into the cyst in women with hemostatic disorders, especially those with severe types. Therefore, ultrasound screening may be indicated in selected women with a high bleeding tendency to allow early detection and appropriate follow-up of the cyst. Future studies are
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required to assess the incidence and the resolution rate of ovarian cysts in women with hemostatic disorders using the LNG-IUS. 6.6. Levonorgestrel intrauterine system and risks of thromboembolism There is currently no evidence available on the risk of venous thromboembolism (VTE) with LNG-IUS. However, data from the World Health Organization Collaborative Study suggests that there is little or no increase in the risk of VTE, stroke or acute myocardial infarction associated with the use of oral or injectable progestogen-only contraceptives [44]. In a case-control study including 74,086 women (younger than 50 years) who received a prescription for a progestogen alone, a positive but nonsignificant association was found between exposure to progestogens alone and VTE [relative risk (RR), 2.4 (95% CI, 0.8–6.5)] [45]. Further analysis in this study showed that high-dose progestogens (5–30 mg) used primarily for menstrual disorders appeared to be associated with an increased risk of VTE [adjusted RR, 5.3 (95% CI, 1.5–18.7)]. However, when progestogens were used for contraception alone, there was no effect on the risk of VTE [adjusted RR, 1.3 (95% CI, 0.3–6.8)]. As plasma concentrations of levonorgestrel achieved by the LNG-IUS are lower than those occurring with Norplant, the combined oral contraceptive and the progestogen-only contraceptives [46–49], the risk of VTE with LNG-IUS would be expected to be none or minimal. The World Health Organization Medical Eligibility Criteria for Contraceptive Use recommends that the benefits of using the LNG-IUS are generally considered to outweigh the potential risks in women with a history of deep-vein thrombosis (DVT) or pulmonary embolus (PE) or known thrombogenic mutations [50]. However, it recommends that in women with current DVT or PE, the risks of using the LNG-IUS generally outweigh the benefits. Due to lack of data on the thrombotic risk of LNG-IUS, it is currently recommended that women with PE or DVT on anticoagulants should be counseled on the potential risk of recurrence of thromboembolic diseases when using progestogen-only contraceptives. This risk, however, should be balanced against the risks of menorrhagia and unwanted pregnancy. 7. Conclusion The LNG-IUS is a reliable contraceptive and is effective in reducing menstrual loss. Current evidence suggests that it is a safe and attractive option for women with hemostatic disorders, which may obviate the need for surgical interventions in these women. Therefore, it should be offered to these women prior to surgical options, especially in the developing countries where surgical intervention carries a higher risk and safe hemostatic agents may not be available or affordable.
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Larger and prospective studies are required to assess the long-term effectiveness of the LNG-IUS, its effects on quality of life and bleeding pattern and the tolerability of its side effects in women with hemostatic disorders. Furthermore, data on its safety in women with thrombotic disorders are needed to reassure the women and their caregiver when using this treatment. Bleeding disorders are relatively uncommon, especially severe types. Therefore, multicenter studies are required to allow inclusion of more women and the attainment of significant data. The establishment of an international registry for the use of the LNG-IUS in women with hemostatic disorders is currently underway via the International Society of Thrombosis and Haemostasis. This will allow clinicians to share their clinical experiences and help them to obtain useful data especially on women with rare disorders.
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R.A. Kadir, C. Chi / Contraception 75 (2007) S123 – S129 [34] Raudaskoski T, Tapanainen J, Tomas E, et al. Intrauterine 10 microg and 20 microg levonorgestrel systems in postmenopausal women receiving oral oestrogen replacement therapy: clinical, endometrial and metabolic response. BJOG 2002;109:136 – 44. [35] Vereide AB, Arnes M, Straume B, Maltau JM, Orbo A. Nuclear morphometric changes and therapy monitoring in patients with endometrial hyperplasia: a study comparing effects of intrauterine levonorgestrel and systemic medroxyprogesterone. Gynecol Oncol 2003;91:526 – 33. [36] Wilemeersch D, Dhont M. Treatment of nonatypical and atypical endometrial hyperplasia with a levonorgestrel-releasing intrauterine system. Am J Obstet Gynecol 2003;188:1297 – 8. [37] Montz FJ, Bristow RE, Bovicelli A, Tomacruz R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am J Obstet Gynecol 2002;186:651 – 7. [38] Xiao B, Wu SC, Chong J, Zeng T, Han LH, Luukkainen T. Therapeutic effects of the levonorgestrel-releasing intrauterine system in the treatment of idiopathic menorrhagia. Fertil Steril 2003;79:963 – 9. [39] Silverberg SG, Haukkamaa M, Arko H, Nilsson CG, Luukkainen T. Endometrial morphology during long-term use of levonorgestrelreleasing intrauterine devices. Int J Gynecol Pathol 1986;5:235 – 41. [40] Hurskainen R, Teperi J, Rissanen P, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291:1456 – 63. [41] Pakarinen P, Suvisaari J, Luukkainen T, Lahteenmaki P. Intracervical and fundal administration of levonorgestrel for contraception: endometrial thickness, patterns of bleeding, and persisting ovarian follicles. Fertil Steril 1997;68:59 – 64.
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[42] Jarvela I, Tekay A, Jouppila P. The effect of a levonorgestrel-releasing intrauterine system on uterine artery blood flow, hormone concentrations and ovarian cyst formation in fertile women. Hum Reprod 1998;13:3379 – 83. [43] Inki P, Hurskainen R, Palo P, et al. Comparison of ovarian cyst formation in women using the levonorgestrel-releasing intrauterine system vs. hysterectomy. Ultrasound Obstet Gynecol 2002;20:381 – 5. [44] World Health Organization P. Cardiovascular disease and use of oral and injectable progestogen only contraceptives and combine injectable contraceptives. Results of an international, multicenter, case control study. Contraception 1998;57:315 – 24. [45] Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999;354:1610 – 1. [46] Nilsson CG, Lahteenmaki PLA, Luukkainen T, Robertson DN. Sustained intrauterine release of levonorgestrel over five years. Fertil Steril 1986;45:805 – 7. [47] Diaz S, Pavez M, Miranda P, Johansson EDB, Croxatto HB. Longterm follow-up of women treated with NorplantR implants. Contraception 1987;35:551 – 67. [48] Kuhnz W, Al-Yacoub G, Fuhrmeister A. Pharmacokinetics of levonorgestrel and ethinylestradiol in 9 women who received a lowdose oral contraceptive over a treatment period of 3 months and, after a wash-out phase, a single oral administration of the same contraceptive formulation. Contraception 1992;46:455 – 69. [49] Weiner E, Victor A, Johansson EDB. Plasma levels of d-norgestrel after oral administration. Contraception 1976;14:563 – 70. [50] World Health Organization (WHO). Medical eligibility criteria for contraceptive use. 3rd ed. Geneva, Switzerland7 WHO; 2004.
Review article
Levonorgestrel intrauterine system: bleeding disorders and anticoagulant therapy Rezan A. Kadir4, Claudia Chi Department of Obstetrics and Gynaecology and Katharine Dormandy Haemophilia Center and Haemostasis Unit, Royal Free Hospital, NW3 2QG London, UK Received 27 December 2006; accepted 19 January 2007
Abstract Hemostatic disorders in women are frequently associated with long-standing menorrhagia. This leads to significant morbidity and adversely affects quality of life. Management of these women poses a particular challenge; medical treatments may be contraindicated, and surgery carries additional risks. The levonorgestrel intrauterine system (LNG-IUS) has been shown to be highly effective in reducing menstrual blood loss in women with normal coagulation. It is also a reliable and reversible contraceptive. Data on the use of this system in women with bleeding disorders or those receiving anticoagulant therapy are limited. Analysis of data from four reported studies suggests that LNG-IUS is a viable and safe option for the management of menorrhagia in these women. Whether the underlying hemostatic disorders lead to a shorter duration of action or prolonged irregular bleeding/spotting post insertion is unknown and requires large prospective studies. Proper counselling remains crucial for patients’ satisfaction. D 2007 Elsevier Inc. All rights reserved. Keywords: Levonorgestrel intrauterine system; Bleeding disorders; Anticoagulant therapy
1. Introduction Disorders of hemostasis are frequently associated with bleeding complications. Women appear to be disproportionately affected with these disorders, and menorrhagia is the most common bleeding symptom. Management of menorrhagia in these women may pose many challenges to clinicians. They may be refractory to many medical treatments, whilst other pharmacological agents can be contraindicated for use. Furthermore, surgical treatment carries additional risks of bleeding or thrombotic complications. The levonorgestrel intrauterine system (LNG-IUS), primarily developed as a contraceptive device, is now increasingly used for the treatment of menorrhagia. With a high efficacy in reducing menstrual blood loss and minimal systemic side effects, it may provide a promising alternate treatment option for these women. This review aims to discuss the magnitude of menstrual disorders affecting women with inherited bleeding disorders
4 Corresponding author. Tel.: +44 020 77940500x35317; fax: +44 020 7830 2799. E-mail address: [email protected] (R.A. Kadir). 0010-7824/$ – see front matter D 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.contraception.2007.01.005
and those receiving anticoagulant therapy. It also addresses the difficulties in treating these women. Finally, it examines the available evidence for the use and effectiveness of LNGIUS in the treatment of menorrhagia and the possible benefits for other gynecological problems. Areas for future research are also explored. 2. Inherited bleeding disorders Inherited bleeding disorders in women are more common than previously suspected. Von Willebrand disease (VWD) is the most common inherited bleeding disorder with a prevalence of approximately 1% in the general population [1,2]. It is generally inherited in an autosomal manner, thus it affects both males and females equally. However, more women with VWD are symptomatic due to the hemostatic challenges of childbirth and monthly menstruation. In the United Kingdom Haemophiila Center Doctors’ Organisation 2005 registry, women accounted for over 60% of the patient registered with VWD. VWD is classified into three main types according to whether the defect in von Willebrand factor (VWF) is quantitative (Types 1 and 3) or qualitative (Type 2). Type 1 is the most common, accounting for
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around 70% of all cases and is characterized by a partial deficiency in VWF. Type 3 involves a near or complete absent of VWF and is therefore severe. This is a rare disorder with a prevalence ranging from 0.1 to 5.3 per million [3]. There are four subtypes (2A, 2B, 2N, 2M) of Type 2 VWD. Type 1 and most Type 2 are transmitted as an autosomal dominant trait, whilst Type 3 and 2N are inherited in a recessive manner. Hemophilia A and B are the most common severe inherited bleeding disorder. They result from deficiencies of coagulation factors VIII and IX, respectively. Their pattern of inheritance is X-linked recessive, hence, men inherit the condition and women are affected as carriers. Carriers of hemophilia are expected to have clotting factor levels around 50% of normal (normal range, 50–150 IU/dL). However, a significant number of carriers have a low factor level and a bleeding tendency. In a study by Plug et al. [4], 27.5% of carriers had a clotting factor level of V 40 IU/dL. These carriers, as well as those with factor levels between 41 and 60 IU/dL, had an increased risk of bleeding compared to noncarriers. A deficiency in other plasma clotting factors (fibrinogen; prothrombin; factor V, VII, X, XI, XIII) or a quantitative or qualitative defect in platelets can also cause bleeding symptoms of varying severity. These rarer coagulation disorders are generally inherited as autosomal recessive traits with severe forms expressed in homozygotes or compound heterozygotes. 3. Menorrhagia in women with hemostatic disorders Disorders of hemostasis are commonly associated with excessive menstrual blood loss. In a survey of 99 women with Type 1 VWD from four hemophilia centers in the United States, 79% reported their periods to be heavy, 71% required medical attention and 13% required hysterectomy for control of menorrhagia [5]. In a study by Ragni et al [6], 93% of 38 women with VWD suffered from heavy menstruation. Menorrhagia was the most common initial bleeding symptom leading to the diagnosis of the disease in 53% of them. In an international survey of 44 women with more severe forms of VWD, 80% had at least one episode of severe menorrhagia requiring blood product therapy [7]. In our center, using the pictorial blood assessment chart (PBAC) [8], menorrhagia (defined by a score of more than 100) was reported in 74%, 57% and 59% of 66 women with VWD, 30 carriers of hemophilia and 20 Factor XI (FXI)deficient women, respectively, compared to 29% in the agematched control group [9]. Women with these disorders also had significantly longer periods (25% bled for more than 8 days compared to only 4% in the control group) and more episodes of flooding and passage of clots [9]. Menorrhagia is a long-standing problem for these women and usually starts from menarche. Menorrhagia since menarche was reported in 65% of women diagnosed with a bleeding disorder, compared to only 9% in those with normal coagulation
[10]. Heavy menstruation has also been reported in women with platelet disorders or a deficiency in prothrombin, fibrinogen, factor V, factor VII, factor X or factor XIII. In a review of published series, menorrhagia was reported in 35– 98% of women with these disorders [11]. Iron deficiency anemia is consequently prevalent among women with bleeding disorders. A past or present history of anemia was reported in 64% of 81 menstruating women with Type 1 VWD, compared with 34% of 150 menstruating controls [5]. There is also a high rate of surgical interventions for menorrhagia, including hysterectomy. A hysterectomy rate of 23–26% has been reported among women with VWD [7,12]. Hysterectomy is often performed at a relatively young age and prior to the diagnosis of the bleeding disorder. There has been a report of hysterectomy as early as 14 years of age [7]. Menstruation also has a significant negative impact on the quality of life of these women. A striking difference in health-related quality of life has been reported between males and females with VWD, with a significantly poorer score in women [13]. It is likely that this burden of morbidity reflects the adverse effects of menorrhagia. Over a third of women with inherited bleeding disorders had to cut down the time spent at work and other activities or accomplished less as a result of their menstruation [14]. Data on menstruation and the prevalence of menorrhagia in women on anticoagulant therapy is very limited. In a small study by van Eijkeren et al. [15], the mean menstrual blood loss measured by the alkaline hematin method was 98 mL (range, 9–239 m/L) in 11 women receiving anticoagulant therapy; five (45%) had menorrhagia (menstrual blood loss of more than 80 mL). Of the six women with normal menstrual loss, two had losses in the high-normal range (60–80 mL). In our center, nine (82%) of the 11 women on anticoagulant therapy had menorrhagia defined by a pictorial blood assessment chart score of greater than 100 (ongoing study). Five women developed intermenstrual bleeding, and six women reported adverse effect on their quality of life during menstruation after the start of their anticoagulant therapy. Choices for contraception and the treatment options of menorrhagia in women on anticoagulant therapy are limited. Combined oral contraceptives are usually contraindicated because of their increased risk of thromboembolic disorders. Copper-containing intrauterine devices are associated with a further increase in menstrual loss. Many clinicians are also very reluctant to use antifibrinolytics in women with a thrombotic tendency. Progestogens alone are therefore the treatment of choice for these women. 4. Levonorgestrel intrauterine system for treatment of menorrhagia in women with hemostatic disorders The LNG-IUS is well established as an effective, longacting and reversible contraceptive. It is associated with a significant reduction in menstrual blood loss as early as the
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first period after insertion [16,17]. It therefore provides an effective treatment modality for menorrhagia and an alternative to surgical interventions for many women. Data regarding the use of LNG-IUS in women with hemostatic disorders is very limited. Literature search revealed only four studies including a total of 69 women [18 – 21]. In our center, the LNG-IUS was used in 16 women with inherited bleeding disorders (13 VWD, two FXI deficiency and one Hermansky-Pudlak syndrome) and menorrhagia not responding to various medical treatments [18]. Nine months after the insertion of the LNG-IUS, nine women became amenorrheic. In the remaining seven women, the PBAC scores decreased significantly from a median of 213 (range 98–386) to 47 (range 24–75). The hemoglobin concentrations increased significantly from a median of 12.1 (range, 8.0–13.2 g/dL) to 13.1 (range, 12.3–14) (p =.0001). No side effects were reported except irregular spotting. The duration of spotting ranged from 30–90 days (median 42 days). Prior to the insertion of the LNG-IUS, the quality of life was adversely affected in all women during their menses for at least 1 day. Nine months after insertion of the LNG-IUS, none of them had any days adversely affected by their menstruation. In another study conducted in New York, the use of LNG-IUS was associated with significant reduction in the menstrual bleeding of 13 women with inherited bleeding disorders (11 VWD, 1 carrier of hemophilia A, 1 platelet function disorder) (Ref. [21] and personal communication with P. Kouides, May 2006). Similarly, there was a significant improvement in the quality of life in all women. The median duration of spotting post insertion was 12 weeks. In one patient, the LNG-IUS was removed at 7 months for this reason. The LNG-IUS was also shown to be an effective treatment for menorrhagia in women receiving oral anticoagulation in a study by Pisoni et al. [20]. Its use was associated with a reduction of menstrual loss in 87% of 16 women receiving warfarin therapy, with a target international normalized ratio between 2.3 and 3.4. Four women became amenorrheic. In addition, there was reduction in the duration of menstruation and the number of sanitary protections used by the women. Most (75%) women felt very satisfied or satisfied with the LNG-IUS. In the study by Schaedel et al. [19], the use of LNGIUS was evaluated in women with various hemostatic disorders including bleeding and thromboembolic disorders. In this retrospective review, 86% (24/28) of the women accepted this form of treatment, including 12 women with bleeding disorders (6 thrombocytopenia, 4 VWD, 1 FXI deficiency and 1 dysfibrinoginemia) and 12 women with thromboembolic disorders, four of whom were on warfarin therapy. The discontinuation rate at 12 months was 21% (5/24). In two women, the LNG-IUS was removed within 7 days due to pain. Another woman developed transverse sinus thrombosis 1 month after LNG-IUS insertion. She was on warfarin treatment for a
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thrombotic disorder, and the LNG-IUS was removed as cautionary. There was one pregnancy with the LNG-IUS in place at 12 months. The last removal was in a woman who experienced worsening menorrhagia following an initial improvement in menstrual blood loss. Among the remaining 19 women, 12 (63%) experienced dramatic clinical improvement with reduced menstrual blood loss or amenorrhoea after the insertion of the first LNG-IUS. The duration of LNG-IUS in place in these women varied between 0.25 and 6 years (median, 4 years). However, seven (37%) women experienced a return of symptoms of varying extent after an initial clinical improvement and required a change of the LNG-IUS after 1–6 years (median duration, 3 years). All of them reported clinical improvement after having the first LNG-IUS removed and another immediately reinserted. A study assessing the long-term effect of LNG-IUS in the management of menorrhagia in women with inherited bleeding disorders is underway in our center. Our preliminary data suggest that this treatment continues to be effective at a median duration of 53 months (range, 24– 60 months) post insertion. The PBAC score of the 13 women, reviewed so far, decreased from a median of 286 (range, 165–386) prior to insertion to a median of 8 (range, 0–77) post insertion; six women were amenorrheic. Their mean hemoglobin concentration increased from 11.5 (range, 10.6–12.9) to 13.1 (range, 11.8–14.2) g/dL. All aspects of quality of life, assessed by a healthrelated quality of life questionnaire [14], were significantly better compared to pre-LNG-IUS insertion. There was one discontinuation at 12 months in a woman who wanted to conceive. Another woman required a change of her LNGIUS because of worsening mastalgia. Her symptom resolved after the replacement of the LNG-IUS.
5. Levonorgestrel intrauterine system for other gynecological problems in women with hemostatic disorders 5.1. Dysmenorrhea Dysmenorrhea is commonly experienced by women with inherited bleeding disorders. Severe or very severe pain during menstruation has been reported in 24% of women with inherited bleeding disorders, compared to 4% in the controls [14]. Nonsteroidal anti-inflammatory drugs are used successfully in the treatment of dysmenorrhea and may also reduce menstrual blood loss in women with menorrhagia. In women with bleeding disorders, especially those with a severe deficiency, this treatment may cause an increase in menstrual blood loss and other bleeding complications due to their antiplatelet effects. Therefore, their use is contraindicated in these women. The LNG-IUS has been shown to be an effective treatment for dysmenorrhea with or without endometriosis [22–25]. In an ongoing study in our center, severe
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dysmenorrhea was reported by 50% of 13 women with inherited bleeding disorders prior to the use of the LNGIUS. When reviewed at 24 months or more after insertion, none had severe dysmenorrhea.
required to establish the efficacy and safety of the LNGIUS in the treatment of these conditions before recommending its routine use.
5.2. Midcycle ovulation pain and bleeding
6. Adverse effects of the levonorgestrel intrauterine system in women with hemostatic disorders
Midcycle pain or Mittelschmerz syndrome was reported by 49% of Type 1 VWD women in a study by Kouides et al. [5]. This pain probably arises from ovulation with subsequent hemorrhage into the corpus luteum or peritoneal irritation due to bleeding from edges of a recently formed corpus luteum. Indeed, acute abdomen due to hemoperitoneum and the extension of bleeding into the broad ligament with spontaneous rupture of the corpus luteum has been reported in patients with bleeding disorders [26,27]. It is important to consider this complication, especially in women with a severe hemostatic disorder such as Type 3 VWD or Glanzmann’s thrombasthenia, before embarking on any surgical intervention. Conservative management with appropriate hemostatic agent has been reported to be successful in avoiding surgery [26]. Suppression of ovulation may be required to prevent recurrence [28]. Combined oral contraceptives are usually used for this purpose. The majority of the menstrual cycles are ovulatory in women using the LNG-IUS. It may therefore be necessary to continue the use of the combined oral contraceptive pill when the LNG-IUS is used for the treatment of menorrhagia or contraception in women with such severe bleeding disorders. 5.3. Other gynecological conditions There is currently very limited data on gynecological problems other than menorrhagia in women with hemostatic disorders. Gynecological problems, especially those manifest with bleeding such as endometriosis, fibroids and endometrial polyps or hyperplasia, were reported more frequently in women with VWD compared to controls in one survey [12]. It is possible that women with bleeding disorders are more likely to become symptomatic with these conditions because of their bleeding tendency. However, large studies are required to assess the association between bleeding disorders and these gynecological problems. The LNG-IUS has been shown to be associated with a reduction in menstrual pain and severity of the disease in women with endometriosis [25,29,30]. A decreased incidence of fibroids following LNG-IUS insertion has also been described [31]. Furthermore, LNG-IUS provides endometrial protection in women taking hormone replacement therapy [31–34], and it is now licensed for this purpose in the United Kingdom and Europe. In addition, promising research indicates regression of endometrial hyperplasia and early-stage endometrial cancer with the LNG-IUS [35–37]. Therefore, the LNG-IUS may have an extended role in managing many gynecological conditions, especially in women with high surgical risks, such as those with hemostatic disorders. However, further studies are
6.1. Complications at insertion Women with bleeding disorders are potentially at risk of bleeding at the time of insertion. Prophylactic treatment for hemostasis should be considered, especially in women with severe bleeding disorders. Women with mild disorders may not require any treatment. In the series by Kouides et al. [21], the procedure was performed without hemostatic cover in 13 women with no bleeding complications. Tranexamic acid (1 g) given 1 h prior to the procedure and continued every 6 h for 24 h is generally sufficient for the majority of women. However, liaison with the hematologist is essential, especially when other form of hemostatic agents such as desmopressin, factor concentrate or platelet transfusion is required. 6.2. Expulsion Total or partial expulsion of the IUS could be due to heavy menstrual blood loss or uterine contractions [38]. Women with hemostatic disorders have very heavy and prolonged periods [9]. Therefore, the use of tranexamic acid during insertion and the first one or two menstrual periods may reduce the risk of this complication in these women. This treatment regimen is currently practiced in our center, and so far, we have had no expulsion in over 25 women with inherited bleeding disorders. 6.3. Irregular spotting/bleeding Irregular and prolonged spotting or mild bleeding in the first 3–6 months after insertion is the main disadvantage of the LNG-IUS. This side effect is a common cause for the discontinuation of treatment. In a systematic review of five randomized controlled trials and five case series on the use of LNG-IUS for the treatment of menorrhagia, the average discontinuation rate at 12 months was 20% in the randomized trials and 17% in the case series [17]. Intermittent intermenstrual bleeding and prolonged bleeding or spotting accounted for 4% and 2% of the discontinuations, respectively. In women with hemostatic disorders, the discontinuation rate among 53 women in the three reported studies was 17% [18,19,21]. Irregular spotting was the main reason for discontinuation in only one of these women [21]. Two women in the study by Schaedel et al. [19] required removal of the original LNGIUS and insertion of a new device for this reason; the spotting settled after replacement of the LNG-IUS. Women with hemostatic disorders and menorrhagia may be more tolerant of this side effect, compared to women with normal menstruation using the LNG-IUS for contraception.
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They have long-standing menorrhagia with chronic iron deficiency anemia. They are generally satisfied with the advantages of reduced menstrual blood loss and improved general health and quality of life achieved with the LNGIUS. Irregular bleeding/spotting with the LNG-IUS was reported in all women (n = 16) in the study by Kingman et al. [18]. Their quality of life after was reported to be better despite this adverse effect. Eleven women did not feel that irregular spotting affected their life, and the remaining five were only slightly affected. Counselling on the potential changes in the bleeding pattern prior to the insertion and reassurance during the follow-up visits that the irregular bleeding will eventually stop improve patients’ acceptability [35]. 6.4. Persistent/recurrent menorrhagia Persistent or recurrent menorrhagia is another reason for treatment discontinuation. LNG-IUS induces atrophy of the endometrial epithelium for more than 5 years [39], which provides a rationale for the reduction of menstrual blood loss. In a study by Xiao et al. [38], the reduction in menstrual loss and the increase in hemoglobin concentrations continued to be significant at the 3-year followup. Similarly, in a randomized controlled trial of the LNG-IUS versus hysterectomy for the treatment of menorrhagia, 48% (57/119) of women still had the LNG-IUS in situ 5 years after randomization with a high satisfaction rate, which was similar to hysterectomy [40]. Discontinuation due to persistent/recurrent menorrhagia was only 16%. In hemostatic disorder-related menorrhagia, data on the duration of effectiveness and rate of symptom recurrence are very limited. In the study by Schaedel et al. [19], 37% of women experienced return of symptoms after an initial clinical improvement. Replacement of the original LNG-IUS with a new device reversed the deterioration in symptoms, and all the women were satisfied with the second IUS. Although based on very limited data, clinicians should consider replacement of the LNG-IUS with another device in women who experience recurrence of heavy bleeding or irregular spotting after an initial positive response. 6.5. Ovarian cysts The use of the LNG-IUS has been reported to be associated with an increased occurrence of ovarian cysts [41–43]. Using transvaginal ultrasound examination, ovarian cysts have been found in 17.5% and 21.5% of women after 6 and 12 months, respectively, of LNG-IUS use [43]. The cysts are asymptomatic and relatively small in size. The majority of these cysts are functional with a high rate of spontaneous resolution. However, there is a potential risk of hemorrhage into the cyst in women with hemostatic disorders, especially those with severe types. Therefore, ultrasound screening may be indicated in selected women with a high bleeding tendency to allow early detection and appropriate follow-up of the cyst. Future studies are
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required to assess the incidence and the resolution rate of ovarian cysts in women with hemostatic disorders using the LNG-IUS. 6.6. Levonorgestrel intrauterine system and risks of thromboembolism There is currently no evidence available on the risk of venous thromboembolism (VTE) with LNG-IUS. However, data from the World Health Organization Collaborative Study suggests that there is little or no increase in the risk of VTE, stroke or acute myocardial infarction associated with the use of oral or injectable progestogen-only contraceptives [44]. In a case-control study including 74,086 women (younger than 50 years) who received a prescription for a progestogen alone, a positive but nonsignificant association was found between exposure to progestogens alone and VTE [relative risk (RR), 2.4 (95% CI, 0.8–6.5)] [45]. Further analysis in this study showed that high-dose progestogens (5–30 mg) used primarily for menstrual disorders appeared to be associated with an increased risk of VTE [adjusted RR, 5.3 (95% CI, 1.5–18.7)]. However, when progestogens were used for contraception alone, there was no effect on the risk of VTE [adjusted RR, 1.3 (95% CI, 0.3–6.8)]. As plasma concentrations of levonorgestrel achieved by the LNG-IUS are lower than those occurring with Norplant, the combined oral contraceptive and the progestogen-only contraceptives [46–49], the risk of VTE with LNG-IUS would be expected to be none or minimal. The World Health Organization Medical Eligibility Criteria for Contraceptive Use recommends that the benefits of using the LNG-IUS are generally considered to outweigh the potential risks in women with a history of deep-vein thrombosis (DVT) or pulmonary embolus (PE) or known thrombogenic mutations [50]. However, it recommends that in women with current DVT or PE, the risks of using the LNG-IUS generally outweigh the benefits. Due to lack of data on the thrombotic risk of LNG-IUS, it is currently recommended that women with PE or DVT on anticoagulants should be counseled on the potential risk of recurrence of thromboembolic diseases when using progestogen-only contraceptives. This risk, however, should be balanced against the risks of menorrhagia and unwanted pregnancy. 7. Conclusion The LNG-IUS is a reliable contraceptive and is effective in reducing menstrual loss. Current evidence suggests that it is a safe and attractive option for women with hemostatic disorders, which may obviate the need for surgical interventions in these women. Therefore, it should be offered to these women prior to surgical options, especially in the developing countries where surgical intervention carries a higher risk and safe hemostatic agents may not be available or affordable.
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Larger and prospective studies are required to assess the long-term effectiveness of the LNG-IUS, its effects on quality of life and bleeding pattern and the tolerability of its side effects in women with hemostatic disorders. Furthermore, data on its safety in women with thrombotic disorders are needed to reassure the women and their caregiver when using this treatment. Bleeding disorders are relatively uncommon, especially severe types. Therefore, multicenter studies are required to allow inclusion of more women and the attainment of significant data. The establishment of an international registry for the use of the LNG-IUS in women with hemostatic disorders is currently underway via the International Society of Thrombosis and Haemostasis. This will allow clinicians to share their clinical experiences and help them to obtain useful data especially on women with rare disorders.
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