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Long-term Follow-up After Endometrial Ablation in Finland: Cancer Risks and Later Hysterectomies

Soini, Tuuli MD; Rantanen, Matti MSc; Paavonen, Jorma MD; Grénman, Seija MD; Mäenpää, Johanna MD; Pukkala, Eero PhD; Gissler, Mika PhD; Hurskainen, Ritva MD

doi: 10.1097/AOG.0000000000002166
Contents: Original Research
Journal Club
ABOG MOC II

OBJECTIVE: To study the risk of endometrial cancer and breast cancer and the hysterectomy rate after endometrial ablation.

METHODS: In this retrospective cohort study, records of all women with endometrial ablation at ages 30–49 years in Finland (1997–2014) were extracted from the Hospital Discharge Register and linked to the Cancer Registry and Finnish Central Population Register. The primary outcome was cancer incidences in the endometrial ablation cohort compared with those in the background population of the same age. Secondarily, the postablation hysterectomy rate was compared with that of a control cohort of similar-aged women extracted from the Finnish Central Population Register. Multivariate regression models with adjustment for age, parity, number of cesarean deliveries, history of sterilization, and the duration of follow-up were evaluated as risk factors for postablation hysterectomy.

RESULTS: In total, 154 cancers (standardized incidence ratio [observed-to-expected ratio] 0.96, 95% CI 0.82–1.13) were diagnosed among 5,484 women treated with endometrial ablation during the follow-up of 39,892 women-years. The standardized incidence ratio for endometrial cancer was 0.56 (95% CI 0.12–1.64) and for breast cancer 0.86 (95% CI 0.67–1.09). A total of 1,086 (19.8%) women had postablation hysterectomy. Risk of hysterectomy was almost fourfold in the endometrial ablation cohort compared with 26,938 women in a control group (adjusted hazard ratio [HR] 3.63, 95% CI 3.32–3.96). Factors predisposing to postablation hysterectomy were leiomyomas (adjusted HR 1.78, 95% CI 1.03–3.10), age younger than 35 years (adjusted HR 1.44, 95% CI 1.15–1.81), at least two prior cesarean deliveries (adjusted HR 1.27, 95% CI 1.04–1.55), and history of sterilization (adjusted HR 1.15, 95% CI 1.01–1.32).

CONCLUSION: Endometrial ablation was not associated with an elevated endometrial cancer or breast cancer risk in Finland. Leiomyomas, young age, and history of prior cesarean deliveries or sterilization were associated with an increased risk of postablation hysterectomy.

Endometrial ablation is not associated with elevated endometrial cancer or breast cancer risk, and most women treated with endometrial ablation do not need later hysterectomy.

Department of Obstetrics and Gynecology, Hyvinkää Hospital, Hyvinkää, the Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, the Department of Obstetrics and Gynecology, Helsinki University Hospital, and the University of Helsinki, Helsinki, the Department of Obstetrics and Gynecology, Turku University Hospital, and the University of Turku, Turku, the Faculty of Medicine and Life Sciences, University of Tampere, the Department of Obstetrics and Gynecology, Tampere University Hospital, and the Faculty of Social Sciences, University of Tampere, Tampere, and the National Institute for Health and Welfare, Department of Information Services, Helsinki, Finland; and the Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Karolinska Institute, Stockholm, Sweden.

Corresponding author: Tuuli Soini, MD, Department of Obstetrics and Gynecology, Hyvinkää Hospital, Sairaalankatu 1, FI-05850 Hyvinkää, Finland; email: tuuli.soini@hus.fi.

Supported by research grants from Cancer Foundation of Finland, Orion Research Foundation, Helsinki University Hospital, and Hyvinkää Hospital.

Financial Disclosure The authors did not report any potential conflicts of interest.

Each author has indicated that he or she has met the journal's requirements for authorship.

Heavy menstrual bleeding is the most common form of abnormal uterine bleeding. It decreases the quality of life of up to 25% of women1 and causes a significant economic burden as a result of the substantial amount of outpatient visits and surgical interventions.1,2 Most patients with heavy menstrual bleeding can be treated with medical therapy or endometrial ablation without hysterectomy.3,4 During the last decades, new nonhysteroscopic endometrial ablation techniques, safe and easy to perform in an outpatient office setting, have replaced the older hysteroscopic endometrial ablation methods.5,6

The effect of endometrial ablation on later risk for cancer, endometrial cancer in particular, is not well known7,8 and population-based studies reporting solely the effect of new nonhysteroscopic endometrial ablations on endometrial cancer do not exist. In addition, it is unknown whether heavy menstrual bleeding is associated with increased risk for breast cancer. Women using a levonorgestrel-releasing intrauterine system for heavy menstrual bleeding have decreased risk for endometrial cancer but increased risk for breast cancer.9,10

Optimally, endometrial ablation relieves heavy menstrual bleeding permanently, but in some cases later hysterectomy is needed.5,11 If the factors predisposing to hysterectomy could be clarified, more individualized risk–benefit estimations could be made before treatment decisions.

Thus, our primary aim of this nationwide study was to assess the risk for endometrial cancer and breast cancer among women treated with endometrial ablation in Finland. Our secondary aim was to identify risk factors for postablation hysterectomy.

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MATERIALS AND METHODS

This study was approved by the institutional review board of Hyvinkää Hospital. The Finnish National Institute for Health and Welfare, after consulting the data protection authority, approved the use of the confidential health register data in this research. The Finnish Central Population Register gave their permission to get the requested data on the patients and to select the women for a control group.

In this observational nationwide cohort study, we collected information on all women in Finland who in 1997–2014 were between the ages of 30 and 49 years and who had undergone endometrial ablation according to the Hospital Discharge Register. Five women in the control group of the same age (±6 months), living in the same area, and alive at the index date were randomly selected for each patient undergoing endometrial ablation from the Finnish Central Population Register to assess the risk for later hysterectomy in the endometrial ablation-treated women and in the general population. The index date was the date of endometrial ablation of the patient. Patients undergoing endometrial ablation with a cancer diagnosis before the beginning of the follow-up and the women in the control group as well as other women in a control group with a cancer diagnosis before the index date were excluded.

All study data were obtained from administrative registers in Finland. The data linkages were done using the unique personal identity code issued by the Finnish Population Register Centre since 1967 to all citizens and permanent residents of Finland and used as the identification key in all national registers.

Data on the endometrial ablations and other surgical procedures were obtained from the registers of the National Institute for Health and Welfare. The information on surgical procedures since 1986 was obtained from the Hospital Discharge Register, which has summary information on patients discharged from public and private hospitals since 1969 with almost 100% coverage,12 and the data accuracy and completeness have been reported to be good.13 The codes of surgical procedures in this register are according to the NOMESCO Classification of Surgical Procedures since 1997. The code LCA 16 (destruction of the endometrium) was used to extract the patients undergoing endometrial ablation from the register. The data about sterilization procedures were obtained from the Sterilization Register kept by the National Institute for Health and Welfare. This register has information in electronic form on all sterilizations performed in Finland since 1987.

The information on all liveborn deliveries was extracted from The Finnish Central Population Register, which has data on all livebirths in Finland in electronic form since 1969. Information on the mode of deliveries was collected from the Medical Birth Register of the National Institute of Health and Welfare, which contains information on all deliveries of livebirths and stillbirths with a gestational age of at least 22 weeks or birth weight of at least 500 g since 1987.

The data on patients with cancer were extracted from the Finnish Cancer Registry, which receives notifications of all patients with cancer from hospitals and pathology laboratories covering virtually 100% of diagnosed cancers in Finland since 1953.14 Since 1961, reporting of patients with a new diagnosis is mandatory by law in Finland. Cancer notifications submitted to the Finnish Cancer Registry are stored in a database and regular quality checks and crosslinkages with the data of the Finnish Central Population Register and cause-of-death data of the Statistics Finland are done to ensure the correctness of data.

Our primary outcomes were all cancer diagnoses after endometrial ablation, especially endometrial cancer and breast cancer. The expected number of cancers was calculated by multiplying the number of women-years in each 5-year age group and calendar period by the corresponding cancer incidence among all Finnish women for each primary cancer site. The women-years at risk were calculated, starting from the date of endometrial ablation and ending on December 31, 2014, or on emigration, or death, whichever occurred first. In addition, censoring at the date of hysterectomy in the analyses for endometrial cancer risk was done. We calculated standardized incidence ratios by dividing the number of observed patients with cancer by the expected number of patients with cancer to assess the cancer risks among endometrial ablation-treated women. Ninety-five percent CIs for the standardized incidence ratios were based on the assumption that the number of observed cases represents a Poisson distribution.15

The secondary outcome was hysterectomy after endometrial ablation. The independent variables for the secondary outcome were the age at the endometrial ablation, parity, number of prior cesarean deliveries, history of prior tubal sterilization, indication of endometrial ablation, and the follow-up time from endometrial ablation. Adjusted hazard ratios (HRs) with 95% CIs for hysterectomy were calculated with a multivariate Poisson regression model using women-years as a model offset. The adjusted multivariate model included the following variables: age at endometrial ablation, parity, number of cesarean deliveries, sterilization, and follow-up time. When comparing the risk for hysterectomy between the endometrial ablation cohort and the control group (ie, women without endometrial ablation), the follow-up for the women in the control group started from the index date of the corresponding patient undergoing endometrial ablation. When estimating the cumulative risk of hysterectomy, we defined death as a competing event that would prevent hysterectomy and estimated cumulative incidence by using a cause-specific hazard method proposed by Putter et al.16

Statistical significance was set at P<.05. Statistical analyses were conducted in statistical program R 3.3.2 using popEpi package 0.4.1.

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RESULTS

During the study period 1997–2014, a total of 5,591 women were treated with endometrial ablation in Finland. After excluding women with a history of cancer before the follow-up and women in the control group (105 women in the endometrial ablation group and 494 matched women in the control group), women with prior cancer in the control group (n=485), and two women with discrepancies in hysterectomy codes in the endometrial ablation group, and 10 women in the control group, the final study cohort included 5,484 endometrial ablation-treated women and 26,938 women in the control group. The mean age (±SD) at endometrial ablation was 42.4±4.4 years (Table 1). The median number of endometrial ablations performed yearly in Finland during the study period was 329 (range 143–511). Over the study period, the number of endometrial ablations increased; during 2010–2014, the growth was approximately 40%. Characteristics of the study cohorts are shown in Table 1. The mean follow-up time was 7.3 years (maximum 18 years).

Table 1

Table 1

In total, 154 patients with a new diagnosis of cancer were diagnosed among the endometrial ablation-treated women during 39,892 women-years at risk (Table 2). The standardized incidence ratio for all cancers was 0.96 (95% CI 0.82–1.13; 154 observed compared with 160 expected cases). The standardized incidence ratio for all cancers in the first year of follow-up was 0.94 (95% CI 0.50–1.61), in 1–5 years 1.00 (95% CI 0.75–1.31), and after 5 years 0.94 (95% CI 0.76–1.16).

Table 2

Table 2

During the study period 1997–2014, the age-standardized incidence rate of endometrial cancer in the Finnish population was 14.2 per 100,000 women-years adjusted for age according to the World Standard Population. After endometrial ablation, the standardized incidence ratio for endometrial cancer was 0.56 (95% CI 0.12–1.64; three observed compared with five expected cases). Of the three patients diagnosed with endometrial cancer after endometrial ablation, two patients were diagnosed at an early stage and one at an unknown stage.

The standardized incidence ratio for breast cancer among endometrial ablation-treated women was 0.86 (95% CI 0.67–1.09; 67 observed compared with 78 expected cases). The standardized incidence ratios for other cancers types were similarly not increased (data not shown).

A total of 1,086 (19.8%) of women treated with endometrial ablation had hysterectomies during the follow-up. Six women (0.1%) had a repeat endometrial ablation during the follow-up. In the control cohort, 2,521 (9.4%) women had hysterectomies during the follow-up. The mean age (±SD) at hysterectomy was 44.7±5.2 years in the endometrial ablation cohort and 44.4±5.7 years in the control cohort. The main indications for hysterectomy after endometrial ablation were heavy menstrual bleeding (47.8%), leiomyomas (18.9%), other unspecified indications (14.0%), dysmenorrhea (9.1%), and endometriosis or adenomyosis (8.0%). In 20 patients (1.8%), the main indication for hysterectomy was endometrial hyperplasia.

The adjusted HR for hysterectomy in endometrial ablation-treated women compared with women in the control group was 3.63 (95% CI 3.32–3.96, P<.001). Compared with the control cohort, the risk for hysterectomy in the endometrial ablation cohort was highest during the first 5 years, but at 10 years after endometrial ablation, the risk was still slightly increased (adjusted HR 1.69, 95% CI 1.13–2.51) (Fig. 1). Postablation hysterectomy risk was highest among women with a history of leiomyoma diagnosis (adjusted HR 1.78, 95% CI 1.03–3.10, P=.016), age younger than 35 years at endometrial ablation (adjusted HR 1.44, 95% CI 1.15–1.81, P=.002), or those with two or more prior cesarean deliveries (adjusted HR 1.27, 95% CI 1.04–1.55, P=.020) or with history of sterilization (adjusted HR 1.15, 95% CI 1.01–1.32, P=.040) (Table 3). The median time from endometrial ablation to hysterectomy was 4.9 years (range 0–18 years). The risk of hysterectomy was highest during the first year after endometrial ablation (adjusted HR 4.44, 95% CI 3.67–5.36, P<.001) and decreased during follow-up (Table 3).

Fig. 1

Fig. 1

Table 3

Table 3

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DISCUSSION

We found that endometrial ablation was not associated with an increased risk for endometrial cancer or breast cancer in Finland. Later hysterectomy was needed only in 19.8% of patients. Young age, leiomyomas, and history of cesarean deliveries or sterilization predicted subsequent hysterectomy. Little is known about the effect of the new nonhysteroscopic endometrial ablation techniques on later cancer risk. In our study, the risk for endometrial cancer was not altered after endometrial ablation.

Only 0.05% of women treated with endometrial ablation were diagnosed with endometrial cancer in our study. This is in line with a Scottish study, which included also first-generation endometrial ablations.7 Singh et al17 found no cases of endometrial cancer among 1,521 women with endometrial ablation with a median follow-up of 10 years, but they did not report whether the follow-up was censored at hysterectomy, after which risk for endometrial cancer disappears. The risk for endometrial cancer among premenopausal women with irregular uterine bleeding has been reported to be increased,18 but an association with heavy menstrual bleeding remains unknown. Our finding of postablation endometrial cancer risk comparable with that of the general population is based on a small number of patients but suggests that no increased risk exists.

Our finding of no effect of endometrial ablation on breast cancer risk is in line with the only previous study.7 In that study, 1.15% of the women with endometrial ablation had a subsequent diagnosis of breast cancer and this was 1.22% in our study. Treatment of heavy menstrual bleeding with a levonorgestrel-releasing intrauterine system was associated with an increased risk for breast cancer,9,10 which could relate to altered intrinsic hormonal factors (ie, hyperestrogenism, chronic anovulation). Our findings, however, imply that heavy menstrual bleeding per se is not a risk factor for breast cancer.

The postablation hysterectomy rate of 19.8% is comparable to previous studies with women of similar age and follow-up (13–20%).7,8,19,20 The need for postablation hysterectomy usually emerges in the first years,7,20 which was also noticed in our study; 75% of hysterectomies were performed during 4 years after endometrial ablation. The risk for hysterectomy was almost four times higher compared with other women of the same age. In several studies, young age at endometrial ablation is a significant risk factor for hysterectomy.19–22 Leiomyomas were a significant risk factor for hysterectomy in our study as well as in a large study from England22 and in a smaller U.S. study.23 We also found that women with postablation hysterectomy were more likely to have prior cesarean deliveries, a finding already reported.20,23 In our study, the majority of women with endometrial ablation were sterilized, which reflects the contraception policy; in Finland, sterilization is strongly recommended before endometrial ablation.

The strengths of this study are the large cohort size, long follow-up, and population-based data from national administrative and health registers with a high level of coverage enabling this type of research.24 We had virtually complete data on all endometrial ablations and other gynecologic operations, cancer diagnoses, and deaths during follow-up minimizing the risk of selection bias. Also, our study represents solely the effects of the new endometrial ablation techniques, which are exclusively used currently with no difference in efficacy compared with the first-generation endometrial ablations.6,25 A limitation was the lack of data on the specific endometrial ablation devices used, but differences in effectiveness among various nonhysteroscopic endometrial ablation devices do not exist.25 In Finland, data on the ethnic background cannot be recorded in the register studies according to current data protection legislation. However, almost all Finns are Caucasian. Hence, we can conclude that the results of our study are generalizable to the Caucasian populations of developed countries.

This study supports the role of endometrial ablation as an effective alternative to hysterectomy in selected women with heavy menstrual bleeding. In most cases, a subsequent hysterectomy can be avoided, although there are factors that predict increased postablation hysterectomy risk. Most importantly, endometrial cancer or breast cancer risk seems to be unaffected by endometrial ablation, which is reassuring when choosing treatment alternatives for heavy menstrual bleeding.

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Figure

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