bleeding
Aarathi Cholkeri-Singh and Keith B Isaacson
10
select group of patients with AUB, and not utilized as a screening tool.
A simpler and less-expensive radiographic tool that is effective for screening is the transvaginal ultrasound (TVUS). With little discomfort and no complications for the patient, this method permits a rapid assessment of the uterus and adnexa. TVUS is useful for measuring endo- metrial thickness in postmenopausal women as well as for detecting uterine myomata and polyps in all women. An endometrial thickness cutoff of ≤5 mm can reliably exclude endometrial cancer in postmenopausal women with a sensitivity as high as 98%. 3,9 The literature shows a wide range of sensitivities and specificities, 21–100%
and 12–100%, respectively, in TVUS detection of intra- uterine pathology. TVUS has reasonable sensitivity for diffuse and focal lesions, so that it may serve as a practical first step in non-invasive diagnosis for AUB. 2
Saline-infused sonohysterogram (SIS) is a minimally invasive technique that enhances the sensitivity and spec- ificity of TVUS. 2,6 It is recommended in patients with either a thick endometrium and a non-diagnostic EMB, an indeterminate TVUS, or a negative TVUS and EMB with persistent bleeding. 2 SIS can be completed within 5–10 minutes with minimal patient discomfort. Even though this technique does not allow for direct visualiza- tion, it has a sensitivity and specificity in detecting uterine cavity lesions comparable to direct visualization as obtained with hysteroscopy. 10–12
Only hysteroscopy (HSC) allows for direct visualiza- tion, accurate diagnosis, and targeted biopsies, leading to reduced sampling errors. 1–3,13 , 14 AUB is the most com- mon indication for outpatient HSC (95.8%) or office HSC (89%). 14 The sensitivity of HSC for diagnosing intrauterine pathology ranges from 53 to 100%, with most literature quoting 80–100%. The specificity of HSC for diagnosing intrauterine pathology ranges from 50 to 100%, with most literature quoting 93–100%. For endo- metrial cancer or hyperplasia detection, the sensitivity and specificity range from 86 to 100% and from 97 to 100%, respectively. The likelihood of endometrial cancer is 0.4–0.5% after a negative hysteroscopy. 3 Table 10.1 shows a comparison of sensitivities and specificities of the imaging modalities based on the reported values of vari- ous studies. Even though the sensitivities and specificities of HSC are similar to the SIS technique, the advantage of HSC is that, while directly visualizing the lesion within the uterine cavity, a direct biopsy or even removal of the lesion can be performed (Figures 10.1 and 10.2). This may eliminate other studies or procedures necessary to diagnose the cause of AUB. Other advantages include the assessment of endometrial vascularity and the categoriza- tion of submucous myomata using different intrauterine pressures (Figures 10.3–10.5). Such presurgical planning
can only be accomplished with the direct view obtained with the hysteroscope.
In a review of 19 studies, Hataska averaged the pro- cedure time of HSC to be about 11 minutes, well-tolerated by patients, with 1/770 cases complicated by a tubal infection. 2 Hysteroscopy can be done in the hospital, as an outpatient surgery, or in the office. In the hospital, the procedure time does not increase but the added time of preoperative registration, anesthesia, procedure, and post- operative recovery lengthen the total time to about 4 hours. By evaluating the patient in the office with HSC, the patient may avoid the operating room time and costs and minimize the disruption in daily activities.
The introduction of small-caliber hysteroscopes in the 1980s has made the office hysteroscope practical. 1 These flexible hysteroscopes have a 2–3.5 mm outer diameter (OD) and permit distal steerability. Using a thumb manipulator, the distal 3–5 cm can typically be deflected 110° in two directions. Because these scopes have small, single-working channels, they are non-continuous flow and are typically used solely for diagnostic purposes. The small diameter (similar to the Pipelle endometrial biopsy) and the steerability create minimal discomfort for the patient. As a result, the uses of a paracervical block and/
or tenaculum are rarely needed in these cases.
Office hysteroscopy can also be performed with stan- dard small-diameter rigid hysteroscopes with an OD of 4–6 mm. The advantage of these systems over the flexible scope is that they are multichanneled and allow for con- tinuous flow of fluid and the passage of instruments such as the semirigid biopsy forceps, scissors, and graspers.
These instruments can be placed through the operative port and allow for visually directed biopsies and small procedures, such as a polypectomy. Most often, intra- venous (IV) anesthesia is not required for procedures util- izing these small-diameter rigid hysteroscopes. Local anesthesia is useful if the cervix is stenotic or requires dilatation prior to insertion of the hysteroscope. How- ever, in patients with a multiparous cervix, cervical dilata- tion is infrequently required and anesthesia is a rare necessity. 15 , 16 The office hysteroscopy procedure is well tolerated without anesthesia even in nulliparous and post- menopausal patients. 15 –17 A vaginoscopic approach to office hysteroscopy requires neither a speculum nor tenac- ulum and may cause less discomfort to the patient. 15–18
Hysteroscopy should be performed in the early follic- ular phase of the menstrual cycle just after menses sub- sides. This is when the endometrium is most thin and visibility optimal. The patient is placed in the dorsal lithotomy position and the vagina prepared with sterile technique. Preferred uterine distention media are either normal saline or lactated ringer’s solutions because they are low-viscosity fluids containing physiologic levels of
Table 10.1 Comparison of imaging sensitivities (Sens) and specificities (Spec) for abnormal uterine bleeding Study Sens Spec Sens Spec Sens Spec Sens Spec Sens Spec D&C D&C HSG HSG TVUS TVUS SIS SIS HSC HSC Valle 1 • Diagnosis of intrauterine pathology 65% 98% Bettocchi et al 21 – 397 patients, mean age 43 years old • Diagnosis of intrauterine pathology 46% 100% Towbin et al 6 – 149 patients, pre/postmenopausal • Diagnosis of intrauterine pathology 80% 85% 54% 90% 79% 93% Widrich et al 10 – 113 patients, pre/postmenopausal • Diagnosis of intrauterine pathology 100% 80% 97% 93% Ceci et al 22 – 443 patients, pre/postmenopausal • Diagnosis of intrauterine pathology 98% 95% Farquhar et al 11 – 2917 patients, 19 studies, pre/postmenopausal • Diagnosis of: intrauterine pathology 46–100% 12–100% 85–100% 81–100% 90–97% 62–93% submucosal myomas 21–100% 53–100% 57–100% 96–100% 53–100% 97–100% endometrial cancer or hyperplasia 33–100% 79–99% 29–80% 82–100% 90–100% 97–100%
Kelekci et al 12 – 50 patients • Diagnosis of intrauterine pathology in women ≥35 years old 56.3% 72.0% 81.3% 100% 87.5% 100% Clark et al 19 – 26346 patients, 65 studies, pre/postmenopausal • Diagnosis of endometrial cancer 86.4% 99% • Diagnosis of endometrial disease 78% 95.8% Bettocchi S et al 13 – 925 patients • Diagnosis of intrauterine pathology in postmenopausal women with: endometrium <4 mm 99% 100% endometrium ≥4 mm 100% 99% Litta et al 9 – 220 patients • Diagnosis of intrauterine pathology in postmenopausal women with endometrial thickness ≥4 mm 55.6% 49.7% 100% 49.6% D&C, dilatation and curettage, HSG, hysterosalpingogram; TVUS, transvaginal ultrasound; SIS, saline-infused sonohysterogram; HSC, hysteroscopy .
electrolytes. At fluid deficit levels of above 1.5 L, fluid overload and pulmonary edema can occur. However, diagnostic hysteroscopy rarely uses more than a total of 500–1000 ml of fluid media even when performing a minor procedure in the office, such as targeted biopsy and polypectomy. If no more than 1.5 L of fluid is used, strict monitoring of fluids is not warranted. If the fluid loss seems to exceed 1.5 L, a diuretic should be administered, urine output closely monitored, and electrolytes drawn.
Diagnostic hysteroscopy in the office or operating room requires minimal setup. For visualization of the cav- ity on a monitor, the hysteroscope is attached to a light source (150–300 W halogen or xenon bulb), light cord, and a single-chip video camera. Video printers are avail- able for printing images captured during the hysteros- copy. In the office, a video tower helps organize this setup.
Figure 10.1 Endometrial cancer
Figure 10.4 Type 1 submucosal myoma
Figure 10.2 Intrauterine polyp
Figure 10.3 Type 0 submucosal myoma
Figure 10.5 Type 2 submucosal myoma
modalities among 149 procedures performed between July 1993 and December 1994. From this study, the average cost of TVUS was US$300–400, HSG US$700, outpatient hospital HSC US$2000, and office HSC US$800. 6 Hidlebaugh did a cost analysis of 473 proce- dures from September 1991 to June 1995 between out- patient hospital HSC and office HSC. The average cost for a hospital HSC was US$1799 (US$1304–2616) and for office HSC was $62 per procedure. 14 Included in the cost analysis were the anesthesia charges for the hospital HSC and the disposable equipment, staff salary, instru- ment repair costs, and capital equipment costs (surgical instruments, hysteroscope, light source, and insufflator) for the office HSC. Fortunately, the Centers for Medicare
& Medicaid Services (CMS) has realized the cost savings to the healthcare system by performing office-based pro- cedures. As a result, new CPT (Current Procedural Ter- minology) codes are expected to become available for these office-based procedures in 2007 that will substan- tially increase the physician reimbursement by covering a facility fee as well as the standard professional fee.
Abnormal uterine bleeding accounts for approximately 33% of women referred to gynecologic clinics, rising to 69% in peri- or postmenopausal women. 12 The role of hysteroscopy in evaluating this common problem contin- ues to be studied and the best diagnostic technique or even combination of techniques is still a debate. The work-up often varies from patient to patient and physi- cian to physician, but each individual patient should be evaluated in a timely and cost-efficient manner.
Contraindications to hysteroscopy include pelvic infec- tions, excessive uterine bleeding, cervical cancer, preg- nancy, and recent uterine perforation. A relative contraindication is known adenocarcinoma of the endo- metrium. Complications of hysteroscopy are minimal, but include bleeding from a tenaculum site or uterine cavity if a small procedure is performed, infection, vasovagal reac- tion, uterine perforation, and creation of a false tract that can lead to perforation or bleeding. These complications typically resolve spontaneously or rarely need treatment:
i.e. silver nitrate or a stitch at a tenaculum site or antibiot- ics for infection. The failure rates for hospital HSC are about 3–3.5%. 14 , 19 Failure rates for office HSC are mini- mal as well, and have been reported from as low as 1%
to as high as 13%. 11,14,19 , 20 The failure rates of 13% for nulliparous women and 11% for postmenopausal women were found in one study of 473 procedures, per- formed in the period 1991–1995, using a rigid, 5 mm OD hysteroscope. 14 The more recent studies have shown a less than 5% failure rate with rigid or flexible office hysteros- copy. 11,19,20 The most common conditions responsible for failure to complete the office hysteroscopy include cervical stenosis, poor visualization, and pain.
Although office hysteroscopy has been shown to be a well-tolerated tool with excellent sensitivity and specific- ity for diagnosing the source of AUB, most gynecologists in the USA continue to perform hysteroscopy in the operating room. The more common office-based evalua- tion tools include the EMB, MRI, HSG, TVUS, and/or SIS. Towbin et al. compared the cost of different imaging
References
1. Valle RF . Office hysteroscopy. Clin Obstet Gynecol 1999 ; 42(2) : 276 – 89 .
2. Hataska H . The evaluation of abnormal uterine bleeding. Clin Obstet Gynecol 2005 ; 48(2) : 258 – 73 .
3. Bradley LD . Abnormal uterine bleeding. Nurse Pract 2005 ; 30(10) : 38 – 49 .
4. Dalfo AR , Ubeda B , Ubeda A, et al. Diagnostic value of hyste- rosalpingography in the detection of intrauterine abnormalities:
a comparison with hysteroscopy. AJR Am J Roentgenol 2004 ; 183 : 1405 – 9 .
5. Preutthipan S , Linasmita V . A prospective comparative study between hysterosalpingography and hysteroscopy in the detec- tion of intrauterine pathology in patients with infertility.
J Obstet Gynaecol Res 2003 ; 29(1) : 33 – 7 .
6. Towbin NA , Gviazda IM , March CM . Office hysteroscopy ver- sus transvaginal ultrasonography in the evaluation of patients with excessive uterine bleeding. Am J Obstet Gynecol 1996 ; 174(6) : 1678 – 82 .
7. Imaoka I , Wada A , Matsuo M, et al. MRI imaging of disorders associated with female infertility: use in diagnosis, treatment, and management. Radiographics 2003 ; 23 : 1401 – 21 .
8. Spielman AL , Keogh C , Forster BB et al. Comparison of MRI and sonography in the preliminary evaluation for fibroid embolization. AJR Am J Roentgenol 2006 ; 187 : 1499 – 504 .
9. Litta P , Merlin F , Saccardi C , et al. Role of hysteroscopy with endometrial biopsy to rule out endometrial cancer in postmeno- pausal women with abnormal bleeding. Maturitas 2005 ; 50(2) : 117 – 23 .
10. Widrich T , Bradley LD , Mitchinson AR , Collins RL . Compari- son of saline infusion sonography with office hysteroscopy for the evaluation of the endometrium. Am J Obstet Gynecol 1996 ; 174(4) : 1327 – 34 .
11. Farquhar C , Ekeroma A , Furness S, et al. A systematic review of transvaginal ultrasonography, sonohysterography and hysteros- copy for the investigation of abnormal uterine bleeding in pre- menopausal women. Acta Obstet Gynecol Scand 2003 ; 82(6) : 493 – 504 .
12. Kelekci S , Kaya E , Alan Y , et al. Comparison of transvaginal sonography, saline infusion sonography, and office hysteroscopy in reproductive-aged women with or without abnormal uterine bleeding. Fertil Steril 2005 ; 84(3) : 682 – 6 .
18. Bettocchi S , Selvaggi L . A vaginoscopic approach to reduce the pain of office hysteroscopy. J Am Assoc Gynecol Laparosc 1997 ; 4(2) : 255 – 8 .
19. Clark TJ , Voit D , Gupta J et al. Accuracy of hysteroscopy in the diagnosis of endometrial cancer and hyperplasia. JAMA 2002 ; 288(13) : 1610 – 21 .
20. Paschopoulos M , Lolis ED , Alamanos Y et al. Vaginoscopic hysteroscopy and transvaginal sonography in the evaluation of patients with abnormal uterine bleeding. J Am Assoc Gynecol Laparosc 2001 ; 8(4) : 506 – 10 .
21. Bettocchi S , Ceci O , Vincino M et al. Diagnostic inadequacy of dilatation and curettage. Fertil Steril 2001 ; 75(4) : 803 – 5 . 22. Ceci O , Bettocchi S , Pellegrino A et al. Comparison of hys-
teroscopic and hysterectomy findings for assessing the diag- nostic accuracy of office hysteroscopy. Fertil Steril 2002 ; 78(3) : 628 – 31 .
13. Bettocchi S , Nappi L , Ceci O et al. The role of office hysteros- copy in menopause. J Am Assoc Gynecol Laparosc 2004 ; 11(1) : 103 – 6 .
14. Hidlebaugh D . A comparison of clinical outcomes and cost of office versus hospital hysteroscopy. J Am Assoc Gynecol Lapa- rosc 1996 ; 4(1) : 39 – 45 .
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17. Bettocchi S , Ceci O , Di Venere R et al. Advanced operative office hysteroscopy without anaesthesia: analysis of 501 cases treated with a 5 Fr. bipolar electrode. Hum Reprod 2002 ; 17(9) : 2435 – 8 .
71 INTRODUCTION
A wide variety of drugs are used to treat abnormal uterine bleeding. Medical therapy is indicated when there is no obvious pelvic abnormality and the woman wishes to retain her fertility. Whereas the number of hysterectomies for menorrhagia has been estimated to have fallen by 36%
between 1989 and 2002/3, and the number of endome- trial ablations is increasing, some women do not wish to have surgery. 1 , 2 Medical treatment avoids surgery, but may have side effects and must be taken long term. 3 Thus, the drug regimen chosen must be effective, have few or mild side effects, and must be acceptable to the patient.
The aims of therapy are to reduce blood loss, reduce the risk of anemia, and improve the quality of life. Menor- rhagia is the commonest cause of iron deficiency anemia in Western women, and thus iron therapy is often indi- cated as well as the options discussed below. It could be argued that menstrual blood loss (MBL) should be reduced to be within the normal range (i.e. less than 80 ml per period). However, women who are keen to avoid surgery may accept a higher loss if they can cope with the flow and any anemia is controlled with iron supplements.
It is important to assess drug therapies in terms of reduction of measured MBL, since, as already discussed in Chapter 5, there is poor correlation between objective and subjective assessment. Well-designed randomized controlled trials provide the best evidence of the efficacy of any intervention, as any differences between groups can be more confidently attributed to differences in treatment.
Medical treatments for abnormal uterine bleeding can be divided into two main classes: non-hormonal and hormonal.
NON-HORMONAL TREATMENTS
Non-hormonal treatments are detailed in Table 11.1.
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) can be chemically classified into five main groups: salicylates (aspirin), indoleacetic acid analogues (indomethacin), aryl- proponic acid derivatives (naproxen, ibuprofen), fena- mates (mefenamic acid, flufenamic acid, meclofenamic acid), and coxibs (celecoxib, rofecoxib). The first four groups inhibit cyclooxygenase-1 (COX-1) and the last cyclooxygenase-2 (COX-2). Interest in the use of NSAIDs started in the early 1980s when the role of uterine prosta- glandins in the genesis of abnormal uterine bleeding was first examined. Excessive levels of prostaglandins were found in menstrual blood and endometrium and prosta- glandin E (a vasodilator) receptor concentrations were significantly higher in women with menorrhagia. 4– 6
NSAIDs have been evaluated in numerous studies, which to date have been limited to COX-1 inhibitors. It is unlikely that COX-2 inhibitors will be studied in view of concerns of cardiovascular risk. 7 Patients subjective perception of improvement and decrease of blood loss has been shown in many placebo-controlled trials. A meta- analysis including 16 randomized studies has provided no evidence that one NSAID is superior to another. 8 Effectiveness in reducing blood loss
Of the NSAIDs, the fenamates (such as mefenamic acid) have been the most extensively studied. The fenamates have the unique property that they inhibit prostaglandin synthesis and also bind to prostaglandin receptors, which are significantly increased in women with menorrhagia. 6 In addition, fenamates are thought to improve endo- metrial hemostasis. 9 Reductions in menstrual blood flow range from 20% to 50%. 10 , 11 Furthermore, treatment continues to be effective long term. A follow-up of 12–15 months after commencing treatment showed that mefenamic acid continued to be effective. 12
Other NSAIDs such as naproxen, ibuprofen, sodium diclofenac, and flurbiprofen also reduce blood loss.