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Obstetrics & Gynecology:
doi: 10.1097/01.AOG.0000296654.43944.e6
Original Research

Follow-up of Women After a First Episode of Postmenopausal Bleeding and Endometrial Thickness Greater Than 4 Millimeters

Timmermans, Anne MD1,2; van Doorn, Lena C. MD, PhD3; Opmeer, Brent C. PhD4; Kroeks, Maurice V. A. M. MD, PhD5; Duk, M Jitze MD, PhD1,6; Bouwmeester, Annette M. MD7; Kruitwagen, Roy F. M. P. MD, PhD8; Dijkhuizen, F Paul H. L. J. MD, PhD9; Mol, Ben W. J. MD, PhD2; for the Dutch Study in Postmenopausal Bleeding (DUPOMEB)

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From the Departments of 1Perinatology and Gynecology, University Medical Centre, Utrecht; 2Obstetrics and Gynecology, Academic Medical Centre, Amsterdam; 3Obstetrics and Gynecology, Erasmus Medical Center, Rotterdam; 4Clinical Epidemiology and Biostatistics, Academic Medical Centre, Amsterdam; 5Obstetrics and Gynecology, Diakonessenhuis, Utrecht; 6Meander Medical Center, Amersfoort; 7Obstetrics and Gynecology, Mesos Medical Center, Utrecht; 8Obstetrics and Gynecology, TweeSteden Hospital, Tilburg; and 9Obstetrics and Gynecology, Rijnstate Hospital, Arnhem, the Netherlands.

*For a list of other members of DUPOMEB, see the Appendix online at www.greenjournal.org/cgi/content/full/111/1/137/DC1.

Supported by grant 01135 from the Healthcare Insurance Board, Amstelveen, the Netherlands.

Corresponding author: A. Timmermans, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; e-mail: a.timmermans@amc.uva.nl.

Financial Disclosure The authors have no potential conflicts of interest to disclose.

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Abstract

OBJECTIVE: To estimate the incidence of recurrent postmenopausal bleeding among women who were diagnosed with an endometrial thickness greater than 4 mm.

METHODS: We designed a prospective cohort study and included consecutive women not using hormone replacement therapy, presenting with a first episode of postmenopausal bleeding. We evaluated patients who had an endometrial thickness greater than 4 mm at transvaginal ultrasonography and benign endometrial sampling; presence of carcinoma was ruled out by office endometrial sampling, hysteroscopy, and/or dilation and curettage. Time until recurrent bleeding was measured, and diagnosis at recurrent bleeding was recorded.

RESULTS: Among 318 patients who had an endometrial thickness greater than 4 mm, 222 patients had benign histology results and were available for follow-up. During follow-up, 47 (21%, 95% confidence interval 16–27%) patients had recurrent bleeding, with a median time to recurrent bleeding of 49 weeks (interquartile range 18 to 86 weeks). There was no difference with respect to recurrence rate between patients with polyp removal, patients with a normal hysteroscopy, and patients with office endometrial sampling alone at the initial workup. Two patients were diagnosed with atypical endometrial hyperplasia upon recurrent bleeding.

CONCLUSION: The recurrence rate of postmenopausal bleeding in women with endometrial thickness greater than 4 mm is 20%. This recurrence rate is not related to incorporation of hysteroscopy or polyp removal at the initial workup.

LEVEL OF EVIDENCE: II

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Postmenopausal bleeding is often caused by abnormalities of the endometrium, being either benign or malignant. Dilation and curettage (D&C) have been used for the diagnosis of endometrial carcinoma in women with postmenopausal bleeding. At present, transvaginal ultrasonography is used as a first step in the evaluation of women with postmenopausal bleeding.1–5 The probability of malignant pathology is strongly reduced in cases wherein the endometrial thickness is less than 5 mm.1,6,7 Above this cutoff level, endometrial sampling is warranted to rule out malignancy.1,6 Office endometrial sampling is a minimally invasive alternative to D&C. It has been shown to be highly accurate in the detection of endometrial carcinoma in women with postmenopausal bleeding, with a sensitivity of 99.6%.8

After malignancy has been ruled out, expectant management can be recommended.3,4 Alternatively, hysteroscopy or sonohydrography can be used to assess the uterine cavity for the presence of benign pathology, mostly endometrial polyps.2–4,9,10 Hysteroscopy or sonohydrography can be incorporated in the diagnostic workup at first episode of bleeding2–4 or in case the bleeding persists or recurs.3,4

Little is known about the recurrence of bleeding in women with postmenopausal bleeding and endometrial thickness more than 4 mm after initial benign sampling. Feldman et al11 reported that 33% of the patients with postmenopausal bleeding and initial benign sampling underwent another sampling during a follow-up of 2 years, but endometrial thickness was not measured in that study. Gull et al12 reported a recurrence of bleeding of 40% during 10 years or more of follow-up in patients with endometrial thickness more than 4 mm and initial benign sampling after a first episode of postmenopausal bleeding.

This issue raises several questions. First, what is the recurrence rate of bleeding after a first episode of postmenopausal bleeding in patients who have an endometrial thickness more than 4 mm and benign histology? Second, does the recurrence rate depend on the performance and outcome of the initial diagnostic workup; that is, do women with a hysteroscopy and/or D&C at the initial workup of postmenopausal bleeding experience less recurrent bleeding than patients with office endometrial sampling only? Third, is malignancy present in women with recurrent bleeding? If the recurrence rate would be low, then a policy with endometrial sampling would be sufficient. If, however, the recurrence rate would be high, or if malignancy would be diagnosed at follow-up, one could advocate that hysteroscopy and/or D&C should be applied immediately. To answer these questions, a prospective cohort study was performed among women not using hormone replacement therapy with a first episode of postmenopausal bleeding, endometrial thickness more than 4 mm, and benign histology. We hypothesized that the recurrence rate among women with normal findings at the initial workup would be low.

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MATERIALS AND METHODS

The study was performed in one university hospital and seven university-affiliated teaching hospitals in the Netherlands. Between January 2002 and June 2003, consecutive patients who presented with a first episode of postmenopausal bleeding at the outpatient department were registered. The study was limited to women not using hormone replacement therapy who had an endometrial thickness more than 4 mm as measured with transvaginal ultrasonography. Data on body mass index (BMI), anticoagulant therapy, comorbidity, endometrial thickness, and histology sampling were recorded.

Patients were evaluated according to the guideline of the Dutch Society of Obstetrics and Gynecology,3 which starts the workup with measurement of endometrial thickness by transvaginal ultrasonography. The thickness of the endometrium was measured from a longitudinal ultrasonogram through the thickest area of the endometrium, measuring the outermost borders of the endometrium. All measurements were done with calipers on a frozen ultrasound image. Measuring the endometrium in postmenopausal women can be difficult due to an upright position of the uterus, vessel calcifications, and a diffuse endometrial–myometrial border. Cases where it was not possible to measure the endometrial thickness in a reliable way were recorded. When the endometrial layers were separated by intracavitary fluid, both layers were measured and the sum recorded.

In patients with an endometrial thickness more than 4 mm and in patients in whom endometrial thickness was not measurable, endometrial sampling was performed, either with an office endometrial sampling device, hysteroscopy with guided biopsies, D&C, or a combination of these tests. Although the national Dutch guideline states that office endometrial sampling alone is sufficient, individual doctors could decide for subsequent testing by hysteroscopy alone or D&C or hysteroscopy combined with D&C. Hysteroscopy and/or D&C were also performed in case office endometrial sampling showed insufficient material for diagnosis. Hysteroscopy and/or D&C were performed as is customary in the residential hospital, which could be in an inpatient setting under general anesthesia or in an outpatient setting with local anesthesia.

Patients whose histology results showed malignancy or atypical hyperplasia were scheduled for further treatment and not included in the follow-up. In cases of benign histology results, expectant management was recommended. The primary endpoint was recurrent bleeding. Each patient was instructed to contact her gynecologist in case the bleeding recurred. In case of recurrent bleeding, the patient was evaluated according to the protocol of the local hospital. From November 2005 until February 2006, hospital records and patients charts were systematically reviewed to assess recurrence of bleeding. Because patients were instructed to contact the hospital in case of recurrent bleeding, it was assumed that if the patients had not contacted the hospital, they had not experienced recurrent bleeding. Time to recurrence of bleeding was censored by this date of chart review if the patient had not contacted the hospital. If the patient had undergone a hysterectomy during the follow-up period for other indications (prolapse surgery) or if the patient had died, this date was taken for censoring.

Time to recurrent bleeding was assessed using Kaplan-Meier analysis. Subsequently, we evaluated whether the performance of a hysteroscopy and/or D&C and the performance of polypectomy at the initial workup were associated with recurrence of bleeding. The log rank statistic was used to test for statistical significance. A P value of less than .05 was considered to indicate statistical significance. If differences were found to be proportional over time, Cox regression analysis was performed and a hazard rate ratio was calculated. Calculations were performed with SPSS 12.0 (SPSS Inc., Chicago, IL).

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RESULTS

We registered 607 patients with a first episode of postmenopausal bleeding, of whom 270 patients had an endometrial thickness more than 4 mm and 48 patients had an endometrial thickness that could not be measured. Histology results showed endometrial carcinoma in 60 patients and atypical endometrial hyperplasia in eight patients. Five patients were diagnosed with other malignancies (three breast cancer metastases, one bladder carcinoma, and one cervical cancer). Four patients were treated for squamous intraepithelial lesions of the cervix, and one patient died shortly after initial workup from a cause not related to her postmenopausal bleeding. Seven patients underwent a hysterectomy for prolapse surgery shortly after their first visit. As a consequence, 233 patients were included in the present study. In 11 of these 233 patients, hospital records were not available or lost; these patients could not be included in the analysis. Patients’ characteristics are summarized in Table 1. From the 222 (95.3%) patients for whom follow-up was known, 107 patients had had office sampling during the initial workup, and 115 patients had had a hysteroscopy with or without a D&C. In 49 of the patients undergoing hysteroscopy, endometrial polyp(s) had been diagnosed and removed (Fig. 1).

Table 1
Table 1
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Fig. 1
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Median duration of follow-up was 176 weeks (interquartile range 156 to 194 weeks, range 50 to 260 weeks). During follow-up, 47 of the 222 (21%, 95% confidence interval [CI] 16–27%) patients had recurrent bleeding (Fig. 1). Median time until recurrent bleeding was 49 weeks (interquartile range 18–86 weeks) (Fig. 2). There were no statistically significant differences in patient characteristics in the recurrent bleeding group when compared with the group of patients without recurrent bleeding. In the group of patients with hysteroscopy and/or D&C, 23 of 115 (20%, 95% CI 14–28%) patients experienced recurrent bleeding, and this was 24 of 107 (22%; 95% CI 16–30%) in the group of patients undergoing office sampling. There was no statistically significant difference with respect to incidence of recurrent bleeding or time to recurrent bleeding between patients with hysteroscopy and/or D&C at initial workup or patients without (Fig. 3), nor was there a difference between patients in whom an endometrial polyp had been identified and removed at initial workup (Fig. 4) and patients in whom such an endometrial polyp was not diagnosed. There were no statistically significant differences in patient characteristics between patients with hysteroscopy and/or D&C at initial workup and recurrent bleeding and patients with office endometrial sampling and recurrent bleeding, nor was there such a difference for patients with polyp diagnosis and removal.

Fig. 2
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Fig. 4
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The subsequent diagnostic process and findings were evaluated for patients with recurrent bleeding. Patients with a hysteroscopy performed at recurrent bleeding had a shorter time to recurrent bleeding (median 32 weeks, interquartile range 18–66 weeks) than patients in whom hysteroscopy at recurrence was not performed (median 64 weeks, interquartile range 49–180 weeks log rank statistics 8.13; P=.004). Cox regression analysis showed a hazard rate ratio of 2.8 (95% CI 1.3–5.8).

At recurrent bleeding two of 47 (4.3%; 95% CI 1.2–14%) patients were diagnosed with atypical endometrial hyperplasia. The first patient was a 53-year-old multipara with diet-regulated diabetes, BMI of 43, and 1.6 years postmenopausal. Office endometrial sampling at initial bleeding episode had shown benign histology; hysteroscopy was also performed at initial workup, during which an endometrial polyp had been removed, also with benign histology. Time to recurrent bleeding was 49 weeks, and atypical hyperplasia was diagnosed with office endometrial sampling. The second patient was a 69-year-old multipara with no history of diabetes or hypertension and BMI of 32, and she was 16 years postmenopausal. Hysteroscopy was performed at initial workup, during which an endometrial polyp was removed, with benign histology. Time to recurrent bleeding was 3.5 years in this patient, and atypical hyperplasia was diagnosed with office endometrial sampling.

In 13 patients, an endometrial polyp was diagnosed at recurrent bleeding. Seven of these patients had not had a hysteroscopy at initial workup. In two patients the hysteroscopy at the initial workup revealed a normal uterine cavity, and the other four patients had had an endometrial polyp removed at the primary workup. The 32 other patients with recurrent bleeding had benign office endometrial sampling or no intracavitary pathology at hysteroscopy.

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DISCUSSION

This study shows that recurrent bleeding in patients with postmenopausal bleeding and endometrial thickness more than 4 mm occurred in 20% of the patients. The median time to recurrent bleeding was approximately 1 year. There was no difference in recurrent bleeding for patients with hysteroscopy and/or D&C at initial workup and patients with office endometrial sampling, nor was there a difference between patients with an endometrial polyp diagnosed and treated at initial workup and patients without a polyp. During follow-up, two (4.3%) endometrial premalignancies were found among patients with recurrent bleeding.

A potential limitation of this study is the fact that patients were not systematically contacted for follow-up. Although patients were instructed to contact the hospital in case of recurrent bleeding, it might be possible that patients experienced recurrent bleeding and did not contact the hospital or were evaluated in another hospital. Therefore, the true incidence of recurrent bleeding might be underestimated. However, it seems highly unlikely that patients would not contact the hospital in case of recurrent bleeding, especially since it is known that patients with postmenopausal bleeding, would like as much certainty as possible in the diagnostic process.13 Furthermore, the Dutch guideline for general practitioners advises to refer patients with postmenopausal bleeding to a gynecologist. Therefore, even if the patient would contact her general practitioner instead of her gynecologist with recurrent bleeding, it would have been highly unlikely if the patient had not been referred to the gynecologist.

Another potential limitation of this study is the fact that initial endometrial sampling procedure was based on clinical choice of the physician. Patients with higher risk profile or more suspicious ultrasound findings (Table 1), may have tended to be treated initially with hysteroscopy rather than office endometrial sampling. However, at recurrent bleeding, patient characteristics were not statistically significantly different between the hysteroscopy group and the office endometrial sampling group; therefore, we think that this did not influence our results. The found absence of significant differences in recurrent bleeding could be explained by the limited power of the current study. Post hoc power analyses indicated, however, that we would have needed a sample size of approximately 1,400 women to detect a reduction in the 5-year recurrence rate from 90% to 85% with an α error of 5% and a β error of 20%.

The incidence of recurrent bleeding in our study (20%) is lower than the incidence found in the study of Gull et al (40%).12 This difference might be explained by the fact that women on hormone replacement therapy were not included in our study, whereas they were included in the study by Gull et al, where 35% of the women used hormone replacement therapy.12 An additional explanation for this difference might be the fact that the follow-up in our study was shorter than in the study by Gull et al, because in that study patients were followed for more than10 years.12 In both our study as well as in the study by Gull et al, follow-up took place by reviewing patients’ medical records and hospital registries.12

In cases where malignant pathology has been excluded by office endometrial sampling without performing hysteroscopy, significant benign pathology, that is, endometrial polyps, may have been overlooked. In patients with postmenopausal bleeding and an endometrial thickness more than 4 mm, the prevalence of endometrial polyps has been reported to be 40%.14,15 Both D&C and office endometrial sampling are known to miss such focal disease.14,16 Imaging of the distended uterine cavity is required to most accurately diagnose focal lesions such as endometrial polyps, and the techniques most often employed are hysteroscopy or sonohydrography.10 Hysteroscopy has the advantage over sonohydrography of allowing simultaneous removal of polyps at the time of diagnosis, although data regarding the efficacy of polypectomy in treating postmenopausal bleeding are scarce.17

In our study, there was no difference in recurrent bleeding between patients with a hysteroscopy incorporated in the initial workup and patients without a hysteroscopy, nor was there a difference between patients with polypectomy at initial workup and patients without a polypectomy. Therefore, with respect to recurrent bleeding symptoms, it is not beneficial for the patient to include a hysteroscopy in the initial workup. Patients’ preference analysis13 showed that if the risk of recurrent bleeding due to benign pathology exceeded 25%, the majority of the patients would prefer a hysteroscopy to diagnose and treat such benign pathology. Because the risk of recurrent bleeding in this study was approximately 20%, it therefore seems justified to refrain from uterine cavity evaluation at the initial workup of postmenopausal bleeding. However, a randomized controlled trial comparing polypectomy with expectant management in cases of postmenopausal bleeding and cost-effectiveness analysis would be needed to fully answer this question.17

The recurrence rate after a first episode of postmenopausal bleeding and endometrial thickness more than 4 mm was estimated to be 20% and not related to incorporation of hysteroscopy or endometrial polyp removal at initial workup. Therefore, the performance of hysteroscopy at the initial workup can be questioned. Endometrial sampling has to be undertaken if patients experience recurrent bleeding, because two patients were diagnosed with atypical endometrial hyperplasia at the time of recurrent bleeding. Further research should focus on the diagnostic workup of women with recurrent postmenopausal bleeding.

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REFERENCES

1. Gupta JK, Chien PF, Voit D, Clark TJ, Khan KS. Ultrasonographic endometrial thickness for diagnosing endometrial pathology in women with postmenopausal bleeding: a meta-analysis. Acta Obstet Gynecol Scand 2002;81:799–816.

2. Epstein E. Management of postmenopausal bleeding in Sweden: a need for increased use of hydrosonography and hysteroscopy. Acta Obstet Gynecol Scand 2004;83:89–95.

3. NVOG Guideline: Abnormal vaginal bleeding during postmenopause [in Dutch]. 2003. Available at: www.nvog.nl/files/lta02_vaginaal_bloedverlies_postmenopauze.pdf. Retrieved October 15, 2007.

4. Scottish Intercollegiate Guidelines Network. Investigation of post-menopausal bleeding. 1st ed. Edinburgh (United Kingdom): Scottish Intercollegiate Guidelines Network, Royal College of Physicians; 2002. Also available at: http://www.sign.ac.uk/guidelines/fulltext/61/index.html. Retrieved October 15, 2007.

5. Goldstein RB, Bree RL, Benson CB, Benacerraf BR, Bloss JD, Carlos R, et al. Evaluation of the woman with postmenopausal bleeding: Society of Radiologists in Ultrasound-Sponsored Consensus Conference statement. J Ultrasound Med 2001;20:1025–36.

6. Smith-Bindman R, Kerlikowske K, Feldstein VA, Subak L, Scheidler J, Segal M, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510–7.

7. Tabor A, Watt HC, Wald NJ. Endometrial thickness as a test for endometrial cancer in women with postmenopausal vaginal bleeding. Obstet Gynecol 2002;99:663–70.

8. Dijkhuizen FP, Mol BW, Brolmann HA, Heintz AP. The accuracy of endometrial sampling in the diagnosis of patients with endometrial carcinoma and hyperplasia: a meta-analysis. Cancer 2000;89:1765–72.

9. Epstein E, Ramirez A, Skoog L, Valentin L. Transvaginal sonography, saline contrast sonohysterography and hysteroscopy for the investigation of women with postmenopausal bleeding and endometrium >5 mm. Ultrasound Obstet Gynecol 2001;18:157–62.

10. Clark TJ. Outpatient hysteroscopy and ultrasonography in the management of endometrial disease. Curr Opin Obstet Gynecol 2004;16:305–11.

11. Feldman S, Shapter A, Welch WR, Berkowitz RS. Two year follow-up of 263 patients with post/perimenopausal bleeding and negative initial biopsy. Gynecol Oncol 1994;55:56–9.

12. Gull B, Karlsson B, Milsom I, Granberg S. Can ultrasound replace dilation and curettage? A longitudinal evaluation of postmenopausal bleeding and transvaginal sonographic mea-surement of the endometrium as predictors of endometrial cancer. Am J Obstet Gynecol 2003;188:401–8.

13. Timmermans A, Opmeer BC, Veersema S, Mol BW. Patients’ preferences in the evaluation of postmenopausal bleeding. BJOG 2007;114:1146–9.

14. Epstein E, Ramirez A, Skoog L, Valentin L. Dilatation and curettage fails to detect most focal lesions in the uterine cavity in women with postmenopausal bleeding. Acta Obstet Gynecol Scand 2001;80:1131–6.

15. Timmermans A, Veersema S. Office hysteroscopy in women with postmenopausal bleeding: see and treat of endometrial polyps using a Duckbill polyp snare. Gynecol Surg 2004;1:189–190.

16. Emanuel MH, Wamsteker K, Lammes FB. Is dilatation and curettage obsolete for diagnosing intrauterine disorders in premenopausal patients with persistent abnormal uterine bleeding? Acta Obstet Gynecol Scand 1997;76:65–8.

17. Nathani F, Clark TJ. Uterine polypectomy in the management of abnormal uterine bleeding: a systematic review. J Minim Invasive Gynecol 2006;13:260–8.

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