El-Nashar, Sherif A. MBBCh1; Hopkins, Matthew R. MD1; Feitoza, Simone S. MD1; Pruthi, Rajiv K. MBBS2; Barnes, Sunni A. PhD3; Gebhart, John B. MD, MS1; Cliby, William A. MD1; Famuyide, Abimbola O. MBBS1
Menorrhagia (excessive menstrual bleeding) is a leading reason for gynecologic office visits in the United States.1 Because of heightened awareness and increased testing, an increasing number of women are receiving a diagnosis of menorrhagia related to bleeding disorders.2 A common presentation in gynecologic practice is excessive vaginal bleeding in association with anticoagulant therapy for thromboembolic prophylaxis and therapy.
Regardless of the cause, vaginal bleeding can be a life-threatening condition, and the coexisting morbidity often limits the treatment options. Medical therapy is frequently contraindicated or ineffective.3 Hysterectomy has been the mainstay of treatment, but significant perioperative hemorrhage poses a great risk.4,5 The ideal treatment option would offer a prompt, simple, and efficacious intervention with a low risk of complications. The newer endometrial ablation technologies allow effective treatment of excessive menstrual loss with less operative risk than hysterectomy.
There is ample evidence that global endometrial ablation is effective and safe in the treatment of menorrhagia in the general population6–10 and in cases with severe bleeding,11–13 but there are only a few case series, with conflicting reports of the effectiveness of endometrial ablation in women with underlying coagulopathy who present with excessive menstrual blood loss.14–16 In the present study, we evaluated the efficacy of global endometrial ablation in treating menorrhagia in women with coagulopathy. We hypothesized that global endometrial ablation is as effective in treating menorrhagia in women with coagulopathy as it is in women without coagulopathy.
PARTICIPANTS AND METHODS
This retrospective cohort study was approved by the Mayo Clinic Institutional Review Board. The medical records–linkage system of Mayo Clinic (Rochester, Minnesota) was used to identify all women who underwent global endometrial ablation from January 1995 through December 2005. Ascertainment of the procedure was done by using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code 68.23 for endometrial ablation.17 A cohort consisting of two groups was constructed: women with coagulopathy (exposed cohort) and a random sample of women without known coagulation defects (unexposed cohort).
The coagulopathy group (exposed cohort) consisted of women with a documented diagnosis of either congenital or acquired bleeding disorders, including von Willebrand disease, inherited bleeding disorders (clotting factor deficiencies), thrombocytopenia (less than 50×109 platelets/L) and abnormal platelet function (as documented with in vitro platelet aggregation studies), and therapeutic or prophylactic use of anticoagulation therapy up to and including the time of ablation therapy.
After women with coagulopathy were identified, the reference group (unexposed cohort) was randomly selected from the remaining pool of women who underwent global endometrial ablation in the predefined period and were not receiving any anticoagulation medication and did not have any documented coagulation abnormality in the period preceding the procedure. Randomization was performed with the simple random row selection function of the JMP 6.0.0 statistical software (SAS Institute Inc, Cary, NC).
The two global endometrial ablation methods used in our institution during this period were thermal balloon ablation technology, brand name ThermaChoice (Gynecare, Somerville, NJ),18 and bipolar radiofrequency ablation technology, brand name NovaSure (Cytyc Surgical Products, Palo Alto, CA).19,20 Individual patient records were reviewed and allocated to one of the groups based on predefined criteria. Women were offered the procedure if an initial trial of medical therapy for menorrhagia had failed or if medical therapy was contraindicated and they had met the U.S. Food and Drug Administration–approved inclusion criteria for global endometrial ablation. Before global endometrial ablation, all women had a thorough clinical examination, a Pap test, endometrial sampling, pelvic ultrasonography, and office hysteroscopy if structural uterine lesions were suspected. Only women with benign polyps or submucous leiomyomas not distorting the endometrial cavity or less than 2 cm in size were offered endometrial ablation; removal was by dilation and curettage or ablation in situ. As is consistent with standard global endometrial ablation practice, none of the women received hormonal or surgical pretreatment of the endometrium. Women receiving anticoagulation were maintained with warfarin up to and through the surgical procedure.
Baseline demographic data were obtained from each patient record, including age, number of previous deliveries (parity), body mass index (BMI), documentation of pretreatment counseling, subjective bleeding amount, pattern of bleeding, presence of coagulation defects, uterine size, uterine position, presence of leiomyomata, endometrial thickness, and endometrial pathology. Coexisting medical morbidities such as diabetes mellitus, malignancy, and cardiovascular disease were abstracted. The technical data elements of interest included the type of ablative technology (balloon ablation technology or bipolar radiofrequency ablation technology) as well as other procedural variables, including total procedural time and mean balloon pressure (in millimeters of mercury) for balloon ablation technology and bipolar radiofrequency ablation technology power settings.
Treatment failure (the primary outcome) was defined as the need for another ablation procedure or hysterectomy during the follow-up period. The ascertainment of treatment failure was done by using two independent methods. First, patient charts were identified by using the following relevant ICD-9-CM codes to determine the occurrence of events of interest: endometrial ablation, 68.23 (at our institution, used exclusively for endometrial ablations only), and the corresponding codes for hysterectomy, including 68.3 (subtotal abdominal hysterectomy), 68.4 (total abdominal hysterectomy), 68.5 (vaginal hysterectomy), 68.6 (radical abdominal hysterectomy), 68.7 (radical vaginal hysterectomy), 68.8 (pelvic exenteration), and 68.9 (other and unspecified hysterectomy). Second, a complete chart review of all the identified subjects (from the first step) was performed to confirm the occurrence of the event of interest (reablation or hysterectomy). Secondary outcome measures included duration of bleeding (in days) and the overall menstrual pattern (amenorrhea, hypomenorrhea, oligomenorrhea, oligohypomenorrhea, polymenorrhea, eumenorrhea, menorrhagia, menometrorrhagia, or no pattern). In addition, pretreatment and posttreatment hemoglobin and ferritin values were recorded. Finally, all documented intraprocedural and late postoperative complications were recorded. Postprocedural mortality was identified through the Rochester Epidemiologic Project Death Data System, and causes of death were reported.
Baseline and demographic data were compared between the coagulopathy and reference groups for confounding factors, including age, parity, type of procedure, amount of bleeding, pattern of bleeding, and duration of follow-up. Mean and standard deviation were used for normally distributed data, and median and interquartile range for skewed data. The independent t test, Wilcoxon rank sum test, χ2 test, and Fisher exact test were used accordingly. Kaplan-Meier survival curves were used with reablation and hysterectomy as events of interest. In anticipation of a lower follow-up rate in the reference group, more women were randomly allocated to this group than to the coagulopathy group. In a two-sided log-rank test with a type I error level of 0.05, a total sample size of 152 women (with unequal samples of 111 and 41) had 83% power to detect a 20% difference in the proportion of treatment failures (ie, 10% versus 30%) between the groups, assuming that 10% were lost to follow-up (nQuery Advisor 4.0, Statistic Solutions, Saugus, MA). The change in the variables was evaluated using the paired t test or the Wilcoxon signed rank test for continuous variables, accordingly. All statistical analyses in this study were performed with JMP 6.0.0 (SAS Institute Inc, Cary, NC).
Of 943 women who underwent global endometrial ablation from January 1995 through December 2005, 42 had preexisting coagulopathy based on the predefined inclusion criteria. One woman was excluded because she withheld consent for research; thus, 41 women (4%) were available in the coagulopathy group for analysis. This included two women with type I von Willebrand disease, five with acquired thrombocytopenia, and 34 receiving warfarin at the time of the procedure. All the women in the coagulopathy group had additional medical conditions or were receiving anticoagulants for serious underlying thrombogenic disorders. The reference group consisted of 111 randomly selected women who underwent global endometrial ablation in the same period. Table 1 describes the baseline characteristics of the study population, and Table 2 lists the indications for anticoagulation. Median follow-up was 24.8 months (interquartile range 11.5–39.3 months). Two women in the coagulopathy group and nine in the reference group were lost to follow-up.
Data were complete for all 152 women for evaluation of the primary outcome. Two women (5%) in the coagulopathy group had hysterectomy or reablation, compared with 8 (7%) in the reference group (Fisher exact test, P=.728). A Kaplan-Meier plot showed no significant difference in the time to treatment failure (reablation or hysterectomy) between the coagulopathy group and the reference group (log-rank test, P=.534) (Fig. 1). Both treatment failures in the coagulopathy group occurred in women taking warfarin at the time of the procedure.
For the secondary outcomes, menstrual history before and after global endometrial ablation was consistently documented in 76 of 152 women. Of these, 64 (84%) reported amenorrhea or light bleeding. The number of days of bleeding per month decreased from 8.5±3.6 days (95% confidence interval [CI] 7.8–9.2 days) to 1.1±2.7 days (95% CI 0.4–1.9 days) (t test, P<.001), and the number of days with intermenstrual spotting or bleeding decreased from 1.8±3.7 days (95% CI 0–4.1 days) to 0.2±0.6 days (95% CI 0.1–0.3 days) (t test, P<.001). Persistent menorrhagia or menometrorrhagia was reported in 12 of 76 women (16%). There was no difference in the amount or pattern of bleeding between the coagulopathy group and the reference group (Table 3 and Fig. 2A). Statistically significant increases in the hemoglobin levels and ferritin levels were observed after the procedure in both groups, with a mean increase of 1.3±1.9 g/dL (95% CI 1–1.7 g/dL) for hemoglobin and 38.9±49.8 mcg/L (95% CI 16.8–61 mcg/L) for ferritin; there was no difference between the groups in the change in hemoglobin (t test, P=.402) and ferritin (t test, P=.257) levels before and after the procedure (Figs. 2B and 2C).
Bipolar radiofrequency ablation technology was used in 77 patients (51%), with a mean power setting of 130±31.7 W (95% CI 123.2–136.8 W) and a mean procedure time of 78±23.1 seconds (95% CI 73.2–83.7 seconds). Balloon ablation technology was used in 75 patients (49%), with a mean pressure of 168.7±8.8 mm Hg (95% CI 165.7–171.8 mm Hg). There was no significant difference between balloon ablation technology and bipolar radiofrequency ablation technology in the proportion of treatment failures (4 of 77 [5%] versus 6 of 75 [8%]; Fisher exact test, P=.526) or in time to treatment failure (log-rank test, P=.852).
Intraprocedural and postprocedural complications were minor and infrequent, with a prevalence of 6% (Table 4). Postprocedural pregnancy was diagnosed in one patient receiving warfarin 60 months after balloon ablation technology endometrial ablation. She subsequently underwent suction curettage for incomplete first-trimester miscarriage. There was no statistically significant difference in the proportion of complications between the coagulopathy group and the reference group (Fisher exact test, P=.267).
Although hysterectomy is effective therapy for menorrhagia, it is associated with serious morbidity in up to 40% of surgical patients.4 Complications include intraoperative and postoperative bleeding, infection, thromboembolism, and damage to adjacent viscera. The incidence and severity of the complications assume a heightened importance in women with coagulopathy who have a bleeding tendency and who often have significant coexisting morbidities (such as malignancies, diabetes mellitus, and morbid obesity) that pose additional anesthetic and surgical risks. Moreover, many in this group require transitioning from long-term anticoagulant therapy to shorter-acting heparin, with the inherent risks of thromboembolism in the perioperative period. Indeed, Torn and Rosendaal5 reported a 12% risk of hemorrhage and thromboembolism in patients receiving oral anticoagulants who were undergoing surgical procedures. These risks were higher in younger patients and in those with mechanical heart valves or atrial fibrillation.
Global endometrial ablation technologies allow effective and safe treatment of menorrhagia with minimal surgical and anesthetic risks. Even although global endometrial ablation is now widely used in the general population, there are only sporadic reports of its use and conflicting evidence of its effectiveness in women with coagulopathy.6–10 In two published case reports, the use of repeated rollerball electrode ablation, as well as thermal balloon ablation, successfully ameliorated menstrual bleeding in women with bleeding disorders.13,14 The largest published study included 11 patients who underwent endometrial resectoscopic ablation. In this study the overall satisfaction rate was high (10 of 11) after 12 months of follow-up.15 Conversely, in a recent report, 3 of 7 patients with von Willebrand disease–related menorrhagia who underwent endometrial ablation required hysterectomies within the first year after ablation.16 Here, we report on a relatively larger cohort of 41 coagulopathy patients who sought treatment for menorrhagia. In contrast to the patients in the previous studies, our patients were older (mean age±standard deviation, 45.9±7.8 years), reflecting the preponderance of patients with acquired bleeding disorders within this cohort.
Using hysterectomy rates and the need for reablation as treatment outcome measures, we found that global endometrial ablation was equally efficacious in the coagulopathy group and the reference group in the treatment of menorrhagia (5% versus 8%). In addition, both groups equally demonstrated a statistically significant reduction in the subjective variables for the evaluation of menstrual blood loss, including the number of bleeding days per month, as well as a significant increase in hemoglobin and ferritin levels.
The prevalence of global endometrial ablation–related complications in this study is consistent with that in the general population. This finding is especially important, given that the coagulopathy group in general had more coexisting morbidities and posed higher anesthetic and surgical risks. However, the minimally invasive nature of global endometrial ablation helps lessen the risk of complications that might be expected if a more invasive procedure, such as a hysterectomy, were performed. In addition, all the patients in the warfarin subgroup (13 of whom had mechanical valves or atrial fibrillation) were fully anticoagulated, up to and including the time of the procedure, obviating the need for an intensive and often laborious perioperative anticoagulant therapy transition.
Another treatment option for women with menorrhagia is placement of the levonorgestrel-releasing intrauterine system. It has been demonstrated in several studies to reduce menstrual blood flow by as much as 97% at 12 months following placement.21 The levonorgestrel system is superior to oral progesterone or mefenamic acid and has treatment efficacy comparable with balloon ablation technology in noncoagulopathy patients presenting with menorrhagia.22–24 Kingman et al25 recently reported on the use of the levonorgestrel system in a subset of 16 women with inheritable bleeding disorders who received a diagnosis of menorrhagia after a questionnaire administered to a known population of patients with bleeding disorders. All reported a significant improvement in bleeding scores and a median increase in hemoglobin concentration of 1 g/dL 9 months after placement. However, because the study involved a screened patient population, it remains unclear whether the levonorgestrel system is effective in patients with bleeding disorders who present with severe menorrhagia or in those who present with severe, acute bleeding. In contrast, all the women in our study presented with menorrhagia, which in some instances was severe enough to warrant hospitalization. Other limitations of the levonorgestrel system include persistent vaginal spotting and a discontinuation rate of 20% at 12 months. Despite its initial efficacy, up to 45% of users undergo hysterectomy within 5 years of placement.22 Nevertheless, the levonorgestrel system may be useful in younger patients who want to retain their reproductive capability.
The main limitation of this study is its retrospective nature. Objective measures of treatment outcomes in women with menorrhagia (such as validated bleeding score and menorrhagia-related quality-of-life questionnaire) were inconsistently documented in our series, but the records-linkage system allowed the use of hysterectomy and reablation rates as surrogates. In addition, preablation and postablation hemoglobin and ferritin levels were accessible and reported. The long observational period of the study is a source of potential bias because two different global endometrial ablation devices were used during this period. However, both devices were found to be equally effective, making the multiplicity of devices used an unlikely confounder. Finally, in spite of the growing number of bleeding disorders diagnosed in association with menorrhagia, the condition is still rare enough to warrant the long observational period of the study.
A systematic review of the MEDLINE, EMBASE, Cochrane Systematic Reviews, CENTRAL, Web of Science, and Scopus databases from inception until April 2006 was performed. This retrospective study is the first and largest cohort study addressing the use of global endometrial ablation in a clinically important and growing population of high-risk women with coagulopathy who present with menorrhagia. Global endometrial ablation appears to be an effective treatment option for these women, especially in the context of coexisting morbidities.
1. Nicholson WK, Ellison SA, Grason H, Powe NR. Patterns of ambulatory care use for gynecologic conditions: a national study. Am J Obstet Gynecol 2001;184:523–30.
2. Amsterdam A, Jakubowski A, Castro-Malaspina H, Baxi E, Kauff N, Krychman M, et al. Treatment of menorrhagia in women undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2004;34:363–6.
3. Chuong CJ, Brenner PF. Management of abnormal uterine bleeding. Am J Obstet Gynecol 1996;175:787–92.
4. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding (Cochrane Review). In: The Cochrane Library, Issue 2, 2006. Oxford: Update Software.
5. Torn M, Rosendaal FR. Oral anticoagulation in surgical procedures: risks and recommendations. Br J Haematol 2003;123:676–82.
6. Lethaby A, Hickey M, Garry R. Endometrial destruction techniques for heavy menstrual bleeding (Cochrane Review). In: The Cochrane Library, Issue 4, 2005. Oxford: Update Software.
7. Feitoza SS, Gebhart JB, Gostout BS, Wilson TO, Cliby WA. Efficacy of thermal balloon ablation in patients with abnormal uterine bleeding. Am J Obstet Gynecol 2003;189:453–7.
8. Busund B, Erno LE, Gronmark A, Istre O. Endometrial ablation with NovaSure GEA: a pilot study. Acta Obstet Gynecol Scand 2003;82:65–8.
9. Gallinat A. NovaSure impedance controlled system for endometrial ablation: three-year follow-up on 107 patients. Am J Obstet Gynecol 2004;191:1585–9.
10. Bongers MY, Bourdrez P, Mol BW, Heintz AP, Brolmann HA. Randomised controlled trial of bipolar radio-frequency endometrial ablation and balloon endometrial ablation. BJOG 2004;111:1095–102.
11. Franchini M, Cianferoni L. Emergency endometrial resection in women with acute, severe uterine bleeding. J Am Assoc Gynecol Laparosc 2000;7:347–50.
12. Richards SR. Endometrial ablation for life-threatening abnormal uterine bleeding: a report of two cases. J Reprod Med 1994;39:741–2.
13. Milad MP, Valle RF. Emergency endometrial ablation for life-threatening uterine bleeding as a result of a coagulopathy. J Am Assoc Gynecol Laparosc 1998;5:301–3.
14. Nichols CM, Gill EJ. Thermal balloon endometrial ablation for management of acute uterine hemorrhage. Obstet Gynecol 2002;100:1092–4.
15. Goldenberg M, Zolti M, Hart S, Bider D. Endometrial resectoscopic ablation in patients with menometrorrhagia as a side effect of anticoagulant therapy. Eur J Obstet Gynecol Reprod Biol 1998;77:77–9.
16. Rubin G, Wortman M, Kouides PA. Endometrial ablation for von Willebrand disease-related menorrhagia: experience with seven cases. Haemophilia 2004;10:477–82.
17. Commission on Professional and Hospital Activities, National Center for Health Statistics (U.S.). H-ICDA; hospital adaptation of ICDA. 2nd ed. Ann Arbor (MI): Commission on Professional and Hospital Activities; 1973.
18. Neuwirth RS, Duran AA, Singer A, MacDonald R, Bolduc L. The endometrial ablator: a new instrument. Obstet Gynecol 1994;83:792–6.
19. Gallinat A, Nugent W. NovaSure impedance-controlled system for endometrial ablation. J Am Assoc Gynecol Laparosc 2002;9:283–9.
20. Cooper J, Gimpelson R, Laberge P, Galen D, Garza-Leal JG, Scott J, et al. A randomized, multicenter trial of safety and efficacy of the NovaSure system in the treatment of menorrhagia. J Am Assoc Gynecol Laparosc 2002;9:418–28.
21. Andersson JK, Rybo G. Levonorgestrel-releasing intrauterine device in the treatment of menorrhagia. Br J Obstet Gynaecol 1990;97:690–4.
22. Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding (Cochrane Review). In: The Cochrane Library, Issue 4, 2005. Oxford: Update Software.
23. Reid PC, Virtanen-Kari S. Randomised comparative trial of the levonorgestrel intrauterine system and mefenamic acid for the treatment of idiopathic menorrhagia: a multiple analysis using total menstrual fluid loss, menstrual blood loss and pictorial blood loss assessment charts. BJOG 2005;112:1121–5.
24. Busfield RA, Farquhar CM, Sowter MC, Lethaby A, Sprecher M, Yu Y, et al. A randomised trial comparing the levonorgestrel intrauterine system and thermal balloon ablation for heavy menstrual bleeding. BJOG 2006;113:257–63.
25. Kingman CE, Kadir RA, Lee CA, Economides DL. The use of levonorgestrel-releasing intrauterine system for treatment of menorrhagia in women with inherited bleeding disorders. BJOG 2004;111:1425–8.